Table of Contents Author Guidelines Submit a Manuscript
Experimental Diabetes Research
Volume 2012, Article ID 749812, 10 pages
http://dx.doi.org/10.1155/2012/749812
Review Article

Signaling Mechanisms in the Regulation of Renal Matrix Metabolism in Diabetes

Division of Nephrology, Department of Medicine, MC7882, South Texas Veterans Healthcare System, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA

Received 5 August 2011; Accepted 2 November 2011

Academic Editor: Theodore W. Kurtz

Copyright © 2012 Meenalakshmi M. Mariappan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Renal hypertrophy and accumulation of extracellular matrix proteins are among cardinal manifestations of diabetic nephropathy. TGF beta system has been implicated in the pathogenesis of these manifestations. Among signaling pathways activated in the kidney in diabetes, mTOR- (mammalian target of rapamycin-)regulated pathways are pivotal in orchestrating high glucose-induced production of ECM proteins leading to functional and structural changes in the kidney culminating in adverse outcomes. Understanding signaling pathways that influence individual matrix protein expression could lead to the development of new interventional strategies. This paper will highlight some of the diverse components of the signaling network stimulated by hyperglycemia with an emphasis on extracellular matrix protein metabolism in the kidney in diabetes.

1. Introduction

The importance of hyperglycemia in renal injury was confirmed by the Diabetes Control and Complications Trial [1] and the United Kingdom Prospective Diabetes Study [2], which demonstrated that diabetic kidney disease can be prevented by keeping blood sugar in target range; however, this is difficult to achieve. Diabetes, particularly type 2, is the most common cause of end-stage renal disease requiring chronic renal replacement therapy in the US. Despite its high prevalence, the mechanism of development and progression of diabetic nephropathy (DN) is still not fully understood, partly because of unrecognized and undiagnosed kidney changes that coexist during latent diabetes [3]. Much of our understanding of the mechanisms of injury in diabetes comes from studies on rodent models of diabetes. Although several such animal models of diabetes exist, no single animal model develops renal changes identical to those seen in humans. Brosius et al. [4] have compiled a report on the progress towards establishing and validating a murine model of human DN (http://www.diacomp.org/). It is likely to be difficult to generate a single mouse model that recapitulates all of the features of human DN.

Pathophysiology of DN involves an interaction of genetic, metabolic, and hemodynamic factors. Structural renal changes in diabetes start with glomerular hypertrophy, followed by glomerular basement membrane (GBM) thickening, mesangial matrix expansion, and development of sclerotic lesions [5]. Accumulation of extracellular matrix proteins is governed by a balance between increased synthesis regulated at the level of transcription and mRNA translation, and, degradation regulated by such processes as the balance between proteolytic activity of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs). A variety of growth factors and cytokines participate in this pathology through complex signal transduction pathways in a cell-specific manner. In this review we will discuss the various mechanisms by which hyperglycemia can induce extracellular matrix synthesis and accumulation in diabetic kidneys.

2. Extracellular Matrix Components

An early sign of renal involvement in diabetes is an increase in basement membrane thickness that has been described as a prediabetic lesion [6]. The thickening of the renal basement membranes of the glomerulus (GBM) and tubules (TBM) is due to a consequence of the hyperglycemia-induced metabolic perturbations resulting in augmented synthesis and accumulation of intrinsic ECM components at these sites [7, 8]. The major TBM components are type IV collagen, laminin, and entactin while collagen types I, V, and VI and fibronectin are generally considered components of the renal interstitium. The GBM is predominantly composed of laminin, collagen type IV alpha 3 to alpha 5, agrin, and perlecan. In diabetes it has been shown that collagen through 5 (IV) chains, collagen V, laminin, fibronectin, and serum proteins contribute to thickened GBM [9]. Mesangial expansion is largely due to the accumulation of extracellular matrix (ECM) proteins such as collagen 1, 2 (IV) chains, collagens V and VI, laminin, and fibronectin [10, 11].

2.1. Laminins

Laminins are glycoproteins expressed primarily in basement membrane. Laminins are heterotrimeric structures consisting of combinations of five alpha, three beta, and three gamma chains that share a common domain and several globular and rod-like domains. The tissue-specific distribution of laminins is mainly determined by expression of the alpha chains; in particular, a number of alpha 5-chain mutations are associated with neonatal lethality and defective glomerulogenesis [12, 13]. Glomerular and proximal tubular epithelial cell laminin expression has been shown to increase in response to hyperglycemia and TGF-b coincident with increased thickening of the glomerular basement membrane [14, 15].

2.2. Collagen Type IV

Collagens serve as fibrotic markers in diabetic nephropathy, and type IV collagen provides the basic structural framework of the glomerular ECM. There are six genetically distinct alpha chains ( 1 through 6), and all have similar domain structures. In the GBM alpha 3 through alpha 5 predominate whereas in the TBM alpha 1, 2, 3, and 5 are present [16, 17].

2.3. Fibronectin

Fibronectin is a glycoprotein that is found in the plasma as well as in the basement membrane and the mesangium of the glomerulus [18, 19]. Types V and VI collagen along with type IV, and fibronectin colocalize in a similar distribution in the glomerular subendothelial area and the mesangium. Entactin/nidogen (En/Nd) is an elongated approximately 150 kDa molecule containing three globular domains separated by two linear segments. Laminin, type IV collagen, and fibronectin are all capable of self-aggregation. Laminin also has additional binding sites for glycosaminoglycans and attaches to collagen via nidogen bridge. It serves as a link between the laminin and collagen IV networks in sub-endothelial, subepithelial and mesangial areas in the glomerular basement membranes [20, 21]. The networking pattern of these ECM components determine the pore size and the charge-selective properties of GBM [22].

3. Role of Transcription, mRNA Translation, and Ribosome Biogenesis in ECM Production

3.1. Transcription

Regulation of protein synthesis may occur at the level of transcription or mRNA translation. High glucose stimulates the transcription of matrix genes and represses matrix degradation leading to glomerulosclerosis [2325]. Sanchez and Sharma [26] have extensively reviewed the mechanism of activation of transcription factors involved in the progression of diabetic kidney disease including upstream stimulatory factors (USF1 and 2), activator protein 1 (AP-1), cAMP-response element-binding protein (CREB), nuclear factor (NF)- B, nuclear factor of activated T cells (NFAT), and stimulating protein 1 (Sp1). Until the beginning of the last decade transcription was the only studied regulatory mechanism for increased ECM protein synthesis induced by hyperglycemia in the renal tissues. Accumulating evidence from recent studies has established mRNA translation as another important and independent step in the regulation of protein synthesis [2730].

3.2. mRNA Translation

The process of mRNA translation occurs in three steps: the initiation phase, which involves localization of the preinitiation complex containing the 40S ribosomal subunit and the initiator methionyl tRNA to the AUG (methionine) codon on the mRNA; the elongation phase, during which amino acids are added to the nascent peptide according the codon sequence of the mRNA; the termination phase, in which arrival at a stop codon leads to the release of the completed peptide chain. Of these three steps, initiation is the rate limiting step as it determines the recruitment of ribosomes to the specific mRNA. Elongation itself is composed of three traditionally defined steps: eEF1A-directed binding of the aminoacyl-tRNA to the A site (aminoacyl site) of the ribosome, peptide bond formation triggered by the enzymatic activity of the ribosome (the peptidyl transferase center), and eEF2- mediated translocation which moves the peptidyl-tRNA from the A site to the P site (peptidyl site) by precisely one codon (three nucleotides) [3133]. Upregulation of these events result in augmented translational efficiency. Signaling pathways play a major role in regulation of translation. Among them the mTOR system regulates the initiation and elongation phases of translation of specific mRNAs to culminate in increased protein synthesis [3133]. Such control is generally exerted through changes in the phosphorylation states of the translation initiation or elongation factors. Diabetic kidney tissues and renal cells treated with high glucose demonstrate activation of various initiation and elongation factors that are involved in regulation of mRNA translation [14, 15, 34]. Activation of these factors by high glucose and angiotensin II resulted in upregulation of selective proteins like laminin beta 1 chain and vascular endothelial growth factor (VEGF), respectively, in tubular epithelial cells [15, 35].

3.3. Ribosome Biogenesis

Ribosome biogenesis is a complex well-coordinated process in which hundreds of different proteins interact in the folding and processing of ribosomal RNA (rRNA) consisting of a small (40S) and large (80S) subunit in eukaryotic cells. The large subunit is composed of 5S, 28S, 5.8S rRNAs whereas the 40S subunit contains 18S rRNA. Furthermore, approximately 80 different ribosomal proteins (r-proteins) are found in eukaryotic ribosomes [36]. Ribosomes consisting of 80S and 40S ribosomal subunits and ribosomal proteins are part of the translation machinery that aid in carrying out the process of peptide synthesis by the addition of amino acids through translation of the genetic code in mRNA. The smaller (40S) subunit of the ribosome serves as a platform to bring together messenger RNA, aminoacylated transfer RNAs, and translation factors. The larger (80S) ribosomal subunit provides peptidyl transferase activity to catalyze peptide bond formation in nascent polypeptides. Increased production of ribosome reflects enhanced capacity for translation. Ribosome biogenesis is so important for cell growth that a growing yeast cell synthesizes approximately 2000 ribosomes every minute, requiring 60% of total cellular transcription. In mammalian cells [37], this number is even higher; for example, a HeLa cell makes 7500 ribosomal subunits per minute [38]. Ribosome biogenesis is regulated by the activity of RNA polymerase I, which controls the rate of rRNA synthesis. The activity of RNA polymerase I at the ribosomal DNA promoter is modulated by a complex of proteins, which includes the nucleolar protein upstream binding factor (UBF) 1. UBF1 interacts with the protein complex TIF-1B (SL1 in humans), which consists of the TATA box-binding protein and three associated factors. The resulting complex promotes the binding of RNA polymerase I to the ribosomal DNA promoter [39, 40]. The activity of UBF1 is regulated, at least in part, by its phosphorylation at Serine 388 [41]. We observed increased UBF phosphorylation at Ser388 accompanied by increased rDNA transcription in glomerular epithelial cells treated with high glucose and in kidney tissues from type 2 diabetic mice model [42]. This eventually leads to increased rRNA molecules and ribosomal proteins thereby increasing translational capacity and sets the stage for increased matrix protein synthesis in renal tissues and cells in response to hyperglycemia.

4. Signaling Pathways Activators and Inhibitors of Protein Synthesis

4.1. mTOR

At the molecular level, mTOR is recognized as the mediator of signals from extracellular high glucose milieu to the nuclear contents of the cell. The complex signaling cascade regulated by high glucose to induce extracellular matrix protein synthesis is summarized in Figure 1. mTOR exists in two distinct physical and functional complexes, namely, mTORC1 and mTORC2 [43]. mTORC1 comprises mTOR, raptor, and mLST8; it phosphorylates the translation initiation regulators, p70S6 kinase and 4E-BP1, resulting in the changes in the activity of a number of initiation and elongation factors [44, 45]. In the resting cell, eukaryotic initiation factor 4E (eIF4E) is held inactive by its binding protein, 4E-BP1 [46]. When a stimulus for protein synthesis is received, mTORC1 is activated and it phosphorylates 4E-BP1. Phosphorylation of 4E-BP1 results in dissociation of eIF4E-4E-BP1 complex and release of eIF4E which then binds to the cap of the mRNA [4750]. This augments the efficiency of translation. Phosphorylation of p70S6 kinase by mTORC1 affects both the initiation and elongation phases of mRNA translation. Activated p70S6 kinase phosphorylates ribosomal proteins and regulates ribosomal function. It also phosphorylates eukaryotic elongation factor 2 kinase (eEF2 kinase) which inhibits its activity [51, 52]. Decreased activity of eEF2 kinase contributes to reduced phosphorylation of eEF2 which results in activation of the latter [53]. As mentioned above, activated eEF2 facilitates the movement of aminoacyl tRNA from the A site to the P site on the ribosome during elongation phase of translation [51]. Thus, activation of p70S6 kinase facilitates the addition of amino acids to the newly synthesized peptide. Kidney tissues from type 2 diabetic db/db mice showed activation of mTORC1 that coincides with renal hypertrophy and matrix expansion. The constituents of the mesangial matrix expansion in the db/db mouse kidney consist of increased type IV collagen, fibronectin, and laminin [54, 55]. We have reported increase in laminin content in glomeruli and tubules by immunohistochemistry and morphometry in db/db mice kidneys when compared to db/m control mice; these diabetes-associated changes were inhibited by rapamycin. Ameliorative effect of rapamycin was shown to be due to inhibition of mTORC1 and its downstream pathways regulating the elongation phase of mRNA translation [34].

749812.fig.001
Figure 1: Intracellular signaling cascades regulated by high glucose leading to activation of promoters and suppression of intrinsic inhibitors of protein synthesis. Grey pentagons show the positive regulators held in an inactive repressor complex with an inhibitory protein. mTORC2 role in high glucose-induced protein synthesis has to be determined.

The mTORC2 complex contains mTOR, rictor, SIN1, and mLST8. Recent work has revealed that it controls the phosphorylation of the antiapoptotic proteins Akt/PKB and serum and glucocorticoid inducible kinase (SGK) and may promote cell survival [5658]. Translation and processing of nascent polypeptides are highly coupled events that result in the production of mature and functional proteins. Recent investigations show that while mTORC2 activation of Akt and SGK1 can modulate translation, this complex also becomes recruited to the translating ribosome in order to process the newly synthesized polypeptide [59, 60]. The ribosome serves as a platform for cotranslational processing, folding, and transporting proteins to their target sites [61].

Most studies so far have been based on pharmacological inhibition of mTORC1 by rapamycin. Systemic administration of rapamycin, a specific and potent inhibitor of mTORC1, ameliorated pathological changes and renal dysfunction in diabetes [14, 6265]. Thus, inactivation of mTORC1 is protective and reduced the effect of Erk- and TGF-beta-mediated prosclerotic pathways. However, cell-specific role of mTOR in renal hypertrophy induced by high glucose remained to be explored. Recent work by G del et al. [66] and Inoki et al. [67] shows that genetic reduction of mTORC1 activity by eliminating 1 Raptor allele prevents podocyte injury and ameliorates the progression of common glomerular diseases such as diabetic nephropathy; mTORC1 activation induced by ablation of an upstream negative regulator Tsc1 recapitulated many DN features, including podocyte loss, glomerular basement membrane thickening, mesangial expansion, and proteinuria in nondiabetic mice. Thus, mTORC1 remains an attractive target for potential therapeutic target to prevent DN.

Increase in protein synthesis occurs not only by stimulation of transcription and translation by also by inhibition of molecules that inhibit these processes. Signaling mechanisms augmenting protein synthesis have received much attention [14, 34, 62, 68, 69]. In contrast, constitutive signaling mechanisms that counteract the prohypertrophic signaling mechanisms and inhibit protein synthesis are not well understood. There are at least three important constitutive inhibitors of protein synthesis. They are AMP-activated protein kinase (AMPK) and Deptor that inhibit the activity of mTOR and glycogen synthase kinase 3 beta (GSK 3 ) that inhibits the activity of eukaryotic initiation factor 2B epsilon (eIF2B ).

4.2. AMPK

AMPK plays a dual role in cell metabolism. It serves as an energy sensor and as a part of AMPK-TSC pathway, it inhibits Rheb/mTORC1 and keeps protein synthesis in check. Hyperglycemia reduced AMPK activity by phosphorylation at Thr172 on the catalytic alpha subunit resulting in activation of mTORC1 in glomerular epithelial cells [14]. Activation of mTORC1 contributes to the renal changes characteristic of DN, including glomerular hypertrophy, glomerular basement membrane (GBM) thickening, and the accumulation of mesangial matrix [14, 7072]. Inhibition of AMPK by high glucose is required for high glucose-induced hypertrophy and ECM protein increment. Treatment of neonatal rat cardiomyocytes and renal glomerular epithelial cells with metformin, AICAR, or resveratrol activated AMPK and inhibited the development of hypertrophy induced by agents such as high glucose or phenylephrine [14, 71, 73]. Thus, AMPK could be a potential target for intervention in diabetic nephropathy.

4.3. GSK

GSK 3 is a ubiquitously expressed, highly conserved serine/threonine protein kinase found in all eukaryotes. Unlike most protein kinases involved in signaling, GSK 3 is active in unstimulated, resting cells and it is inactivated upon phosphorylation at Serine 9. GSK 3 is inactivated during hypertrophy of skeletal myotube [74], heart [75, 76] and pulmonary artery smooth muscle [77]. GSK 3 phosphorylates its substrate eIF2B epsilon in the resting cell [78]. Activity of eIF2B epsilon is important for the formation of the preinitiation complex during the initiation phase of mRNA translation [79]. We observed that GSK 3 inhibits high glucose-induced protein synthesis in renal proximal tubular epithelial cells and renal tissues by inhibiting the activity of eIF2Bε [80]. Type 2 diabetic db/db mice showed increased phosphorylation of renal cortical GSK 3 and decreased phosphorylation of eIF2Bε, which correlated with renal hypertrophy at 2 weeks, and increased laminin 1 and fibronectin protein content at 2 months. These data raise the possibility that renal hypertrophy and laminin 1 accumulation induced by type 2 diabetes could be rescued by the activation of GSK 3 or by overexpression of an active form of GSK 3 in the kidney in the db/db mouse. In transgenic mice overexpressing activate form of GSK 3β in the heart, the hypertrophic response to calcineurin activation was severely impaired [81]. However, it is interesting to note that transgenic mice overexpressing constitutively active form of GSK 3 (GSK3S9A/S21A knockin mice) exhibit glomerular injury with proteinuria [82].

4.4. Emerging Target in Signaling

Deptor (DEPDC6-DEP domain-containing and mTOR-interactive protein) is a novel mTOR regulatory protein that interacts with mTOR in both mTORC1 and mTORC2 and negatively regulates mTOR activity [83, 84]. As discussed earlier, mTORC1 is a central regulator of protein synthesis, ribosome biogenesis and cell growth during diabetic kidney. A series of elegant experiments based on loss-of-function strategy by Peterson et al., [85] showed that Deptor interacts directly with both mTOR complexes and inhibits downstream pathways regulated by both complexes. Liu et al., [86] have shown that enhanced interaction between mTOR and Deptor by resveratrol, a known inhibitor of mTORC1 [70], negatively regulated leucine-induced mTORC1 signaling in C2C12 myoblasts. Finally Deptor knockdown in vivo largely prevented the atrophic response produced by immobilization and, in part, this response was mediated by an increased muscle protein synthesis [87]. Given its powerful role as mTOR regulator, investigating the role of Deptor in diabetic kidney disease may provide a new avenue for preventing renal matrix accumulation.

5. Micro RNA (miR) in ECM Synthesis and Accumulation

miR microarray identified five miRs (192, 194, 204, 215, and 216) that were highly expressed in human and mouse kidney [88]. A seminal report by Kato et al. demonstrated that the expression of miR 192, one of the highly expressed miRs in the mouse kidney, is increased in the glomeruli from db/db type 2 diabetic mice when compared to control mice [89, 90] and in mesangial cells treated with high glucose [91]. Upregulated expression of miR 192 occurs as a consequence of TGF beta increment in diabetic glomeruli which in turn increased the expression of Col1a2. Wang et al. [91] demonstrated that in cultured human MCs exposed to high glucose or TGF-beta, as well as in mouse DN models in vivo, there was a significant upregulation of miR-377 that indirectly led to enhanced fibronectin production. Long et al. [92] identified miR-29c expression in the kidney glomeruli obtained from db/db type 2 diabetic mice in vivo and in kidney microvascular endothelial cells and podocytes treated with high glucose in vitro that has been found to enhance ECM protein accumulation.

Recent studies have elucidated the role of miRs in controlling translation [93]. miRs regulate gene expression by inhibiting translation and/or by inducing degradation of target messenger RNAs [94]. miRs bind directly to 3′ untranslated regions of specific transcripts and most often directly repress translation; furthermore, an mRNA can be simultaneously repressed by more than one miRNA species or one miRNA can modulate more than one transcript [95]. Programmed cell death 4 (PDCD4), an endogenous inhibitor of translation, has been identified as a target of miR 21, and it will be interesting to investigate the role of miR 21 in regulating ECM protein synthesis induced by diabetes. Dey et al. [96] reported that high glucose and TGFβ increase miR-21 and miR-214 in mesangial and proximal tubular epithelial cells. These microRNAs target downregulation of PTEN, an endogenous inhibitor of PI3 kinase dependent downstream Akt activity, for translational repression. The field of miRs and their role in diabetic kidney disease are an emerging field of investigation, and further studies will unravel the regulatory mechanism of these so-called “junk” DNA sequences in the genetic code [97].

6. Epigenetic Modification in ECM Production

Epigenetics is defined as mechanisms that affect chromatin structure and gene expression and dysregulation of the epigenome can also lead to disease. Major pathologic mediators of diabetes such as hyperglycemia, inflammatory factors, cytokines, and growth factors can lead to dysregulation of epigenetics [98]. Epigenetic changes include DNA methylation (covalent attachment of methyl groups at CpG dinucleotides), histone modifications (acetylation, methylation, phosphorylation, and ubiquitination), and RNA-based silencing. In the context of diabetic nephropathy, the altered state of the epigenome may be the underlying mechanism contributing to a “metabolic memory” that results in chronic inflammation and vascular dysfunction in diabetes even after achieving glycaemic control [99101]. Identification of genetic and epigenetic risk factors that modulate ECM protein expression individually could provide the basis for the development of novel treatments and newer animal models of diabetic nephropathy.

7. Renal ECM Metabolism in Animal Models of Type 2 Diabetes

A higher proportion of individuals with type 2 diabetes are found to have microalbuminuria and overt nephropathy shortly after the diagnosis of their diabetes, because diabetes is actually present for many years before the diagnosis. This is why animal models of type 2 diabetes are very important so that newer and specific markers of early kidney injury could be identified before clinical diagnosis of the disease. However, these animals could only recapitulate some of the features of diabetic kidney disease seen in humans [102, 103]. T2DM is a complex genetic disease comprising many metabolic disorders with a common phenotype of glucose intolerance. Cohen et al. [104] have documented that glomerular pathology in type 2 diabetic db/db mice is accompanied by definable alterations in renal function, which are similar in chronology and nature to those found in human diabetes. Studies in db/db mice with type 2 diabetes have shown that accumulation of the renal matrix protein laminin-beta 1 is not associated with increase in its mRNA, suggesting potential regulation by mRNA translation [54]. Since hyperglycemia is associated with hyperinsulinemia, coinciding with the onset of laminin accumulation in the kidney in db/db mice, augmented laminin mRNA translation could be due to either elevated glucose or high insulin. If hyperinsulinemia was to be implicated in laminin regulation in type 2 diabetes, the renal parenchyma would have to be responsive to insulin, unlike the liver which is insulin resistant. This was investigated by Feliers and colleagues; they employed a series of tests examining the status of insulin receptor activation and reported that kidney is responsive to insulin at the same time when liver is resistant to insulin in diabetic db/db mice [105]. These observations steered a series of investigations that identified a novel regulatory mechanism for ECM protein increment, mRNA translation [14, 15, 32], and also raised the possibility that hyperinsulinemia could participate in renal injury in type 2 diabetes.

There are two other models of type 2 diabetes which show progression of diabetic kidney disease that resemble human disease. The KKAy/Ta mice produced by transfection of the yellow obese gene (Ay) into KK/Ta mice are obese, diabetic mice that manifest hyperglycemia, hypertriglyceridemia, hyperinsulinemia, and microalbuminuria. KKAy mice developed hyperglycemia, hyperinsulinemia, and obesity after 16 weeks, with proteinuria, mesangial matrix accumulation, GBM thickening, and tubular dilation. It was considered a good animal model for the early pathology changes of DN [106108]. The MKR mice which transgenically express mutant IGF-1R specifically in skeletal muscle develop insulin resistance in fat and liver with rapidly progressive beta-cell dysfunction and type 2 diabetes [109]. They exhibit early onset of the disease phenotype as seen by insulin resistance (as early as 4 weeks), fasting hyperglycemia (from 5 weeks), and abnormal glucose tolerance (at 7–12 weeks), and they develop kidney disease characterized by ECM accumulation [110].

8. Management of Diabetic Renal Disease

Currently available therapies are not completely effective in arresting progression of diabetic kidney disease, especially at more advanced stages of disease. Consistent with investigations discussed above [35], studies have shown that ACE inhibitors and ARBs are beneficial in reducing the progression of albuminuria in patients with type 2 diabetes [5, 72, 111]. Treatment with an ACE inhibitor has been shown to normalize expression of laminin in murine mesangial cells [112]. A recent report shows the use of antifibrogenic drugs that block TGF beta to be effective in restoring kidney function [113]. Although the angiotensin-converting enzyme inhibitors and angiotensin receptor blockers retard the progression of diabetic nephropathy, they are not able to halt the eventual development of end-stage renal disease [114, 115]. One reason could be that pathological changes in the kidney may already be in place preceding the clinical diagnosis of diabetic nephropathy owing to the cumulative effects of postprandial hyperglycemic excursions, metabolic syndrome, and insulin resistance in type 2 diabetes. We need to take into consideration that several pathologic processes work in consort to result in kidney injury in diabetes. To date the usual investigational approach has been linear, having adopted the traditional one-variable-at-a-time model. Future investigations should apply a systems biology approach to understand how multiple pathogenetic events occurring simultaneously result in renal injury in diabetes.

9. Conclusion

Deregulation of protein synthesis, processing, and degradation underlie the development of renal matrix changes induced by hyperglycemia in type 2 diabetes. Thus, attenuating ECM accumulation and/or enhancing ECM degradation is considered a prime target in the preventive treatment of diabetic renal complications. In order to achieve this objective identifying the molecular mechanisms by which high glucose stimulates matrix protein synthesis is of paramount importance. Understanding these mechanisms may help develop early detection strategies and help identify those subjects at risk of progressing to advanced kidney derangement. While optimal control of hyperglycemia is a highly desirable approach in the treatment of diabetic complications including nephropathy, the difficulty in achieving this goal due to inability to adhere to therapeutic regimens and adverse effects of intensive glucose control regimens require us to find additional therapeutic avenues. Such interventions can only be developed by truly understanding the pathogenesis of kidney injury in diabetes and identifying viable therapeutic targets.

Abbreviations

ECM:Extracellular matrix protein
DN:Diabetic nephropathy
GBM:Glomerular basement membrane
TBM:Tubular basement membrane
4E-BP:4E binding protein
AICAR:5-aminoimidazole-4-carboxamide 1- -ribofuranoside
AMPK:AMP-activated protein kinase
eEF:Eukaryotic elongation factor
eIF:Eukaryotic initiation factor
G L:G protein -subunit-like protein
GEC:Glomerular epithelial cells
TGF :Transforming growth factor beta
IGF:Insulin-like growth factor
mTOR:Mammalian target of rapamycin
PTEN:Phosphatase and tensin homolog on chromosome ten
Raptor:Regulatory associated protein of TOR
Rheb:Ras homolog enriched in brain
TSC:Tuberous sclerosis complex
UTR:Untranslated region
UBF1:Upstream binding factor 1
VEGF:Vascular endothelial growth factor
PDCD4:Programmed cell death 4.

Acknowledgments

The author thanks his mentor Dr. B. S. Kasinath for critically reading the paper and for giving comments and advice. Work contained in this paper was supported by the NIH, VA merit review program, and American Diabetes Association awarded to B. S. Kasinath and Juvenile Diabetes Research Foundation and the National Kidney Foundation of South and Central Texas awarded to M. M. Mariappan. The author regrets that due to space limitations many seminal publications could not be cited.

References

  1. “The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group,” The New England Journal of Medicine, vol. 329, no. 14, pp. 977–986, 1993.
  2. “Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group,” The Lancet, vol. 352, no. 9131, pp. 854–865, 1998.
  3. R. J. Middleton, R. N. Foley, J. Hegarty et al., “The unrecognized prevalence of chronic kidney disease in diabetes,” Nephrology Dialysis Transplantation, vol. 21, no. 1, pp. 88–92, 2006. View at Publisher · View at Google Scholar · View at Scopus
  4. F. C. Brosius III, C. E. Alpers, E. P. Bottinger et al., “Mouse models of diabetic nephropathy,” Journal of the American Society of Nephrology, vol. 20, no. 12, pp. 2503–2512, 2009. View at Publisher · View at Google Scholar · View at Scopus
  5. M. E. Molitch, R. A. DeFronzo, M. J. Franz et al., “Nephropathy in diabetes,” Diabetes Care, vol. 27, supplement 1, pp. S79–S83, 2004. View at Google Scholar
  6. F. M. M. Lai, C. C. Szeto, P. C. L. Choi et al., “Isolate diffuse thickening of glomerular capillary basement membrane: a renal lesion in prediabetes?” Modern Pathology, vol. 17, no. 12, pp. 1506–1512, 2004. View at Publisher · View at Google Scholar · View at Scopus
  7. R. M. Mason and N. A. Wahab, “Extracellular matrix metabolism in diabetic nephropathy,” Journal of the American Society of Nephrology, vol. 14, no. 5, pp. 1358–1373, 2003. View at Publisher · View at Google Scholar · View at Scopus
  8. F. N. Ziyadeh, “Renal tubular basement membrane and collagen type IV in diabetes mellitus,” Kidney International, vol. 43, no. 1, pp. 114–120, 1993. View at Google Scholar · View at Scopus
  9. A. Nerlich and E. Schleicher, “Immunohistochemical localization of extracellular matrix components in human diabetic glomerular lesions,” American Journal of Pathology, vol. 139, no. 4, pp. 889–899, 1991. View at Google Scholar · View at Scopus
  10. S. H. Ayo, R. A. Radnik, J. A. Garoni, W. F. Glass, and J. I. Kreisberg, “High glucose causes an increase in extracellular matrix proteins in cultured mesangial cells,” American Journal of Pathology, vol. 136, no. 6, pp. 1339–1348, 1990. View at Google Scholar · View at Scopus
  11. J. H. Miner, “Renal basement membrane components,” Kidney International, vol. 56, no. 6, pp. 2016–2024, 1999. View at Publisher · View at Google Scholar · View at Scopus
  12. M. Durbeej, “Laminins,” Cell and Tissue Research, vol. 339, no. 1, pp. 259–268, 2010. View at Publisher · View at Google Scholar · View at Scopus
  13. J. H. Miner and C. Li, “Defective glomerulogenesis in the absence of laminin α5 demonstrates a developmental role for the kidney glomerular basement membrane,” Developmental Biology, vol. 217, no. 2, pp. 278–289, 2000. View at Publisher · View at Google Scholar · View at Scopus
  14. M. J. Lee, D. Feliers, M. M. Mariappan et al., “A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy,” American Journal of Physiology, vol. 292, no. 2, pp. F617–F627, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. M. M. Mariappan, D. Feliers, S. Mummidi, G. G. Choudhury, and B. S. Kasinath, “High glucose, high insulin, and their combination rapidly induce laminin-β1 synthesis by regulation of mRNA translation in renal epithelial cells,” Diabetes, vol. 56, no. 2, pp. 476–485, 2007. View at Publisher · View at Google Scholar · View at Scopus
  16. Y. Kim, M. M. Kleppel, R. Butkowski, S. M. Mauer, J. Wieslander, and A. F. Michael, “Differential expression of basement membrane collagen chains in diabetic nephropathy,” American Journal of Pathology, vol. 138, no. 2, pp. 413–420, 1991. View at Google Scholar · View at Scopus
  17. E. C. Tsilibary, “Microvascular basement membranes in diabetes mellitus,” Journal of Pathology, vol. 200, no. 4, pp. 537–546, 2003. View at Publisher · View at Google Scholar · View at Scopus
  18. P. J. Courtoy, Y. S. Kanwar, R. O. Hynes, and M. G. Farquhar, “Fibronectin localization in the rat glomerulus,” Journal of Cell Biology, vol. 87, no. 3, pp. 691–696, 1980. View at Google Scholar · View at Scopus
  19. E. Ruoslahti, E. Engvall, and E. G. Hayman, “Fibronectin: current concepts of its structure and functions,” Collagen and Related Research, vol. 1, no. 1, pp. 95–128, 1981. View at Google Scholar · View at Scopus
  20. A. E. Chung and M. E. Durkin, “Entactin: structure and function,” American Journal of Respiratory Cell and Molecular Biology, vol. 3, no. 4, pp. 275–282, 1990. View at Google Scholar · View at Scopus
  21. R. Timpl, “Macromolecular organization of basement membranes,” Current Opinion in Cell Biology, vol. 8, no. 5, pp. 618–624, 1996. View at Publisher · View at Google Scholar · View at Scopus
  22. S. Adler, “Structure-function relationships associated with extracellular matrix alterations in diabetic glomerulopathy,” Journal of the American Society of Nephrology, vol. 5, no. 5, pp. 1165–1172, 1994. View at Google Scholar · View at Scopus
  23. S. Y. Han, Y. H. Jee, K. H. Han et al., “An imbalance between matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 contributes to the development of early diabetic nephropathy,” Nephrology Dialysis Transplantation, vol. 21, no. 9, pp. 2406–2416, 2006. View at Publisher · View at Google Scholar · View at Scopus
  24. M. Haneda, D. Koya, M. Isono, and R. Kikkawa, “Overview of glucose signaling in mesangial cells in diabetic nephropathy,” Journal of the American Society of Nephrology, vol. 14, no. 5, pp. 1374–1382, 2003. View at Publisher · View at Google Scholar · View at Scopus
  25. Y. Liu, K. Rajur, E. Tolbert, and L. D. Dworkin, “Endogenous hepatocyte growth factor ameliorates chronic renal injury by activating matrix degradation pathways,” Kidney International, vol. 58, no. 5, pp. 2028–2043, 2000. View at Publisher · View at Google Scholar · View at Scopus
  26. A. P. Sanchez and K. Sharma, “Transcription factors in the pathogenesis of diabetic nephropathy,” Expert Reviews in Molecular Medicine, vol. 11, article e13, 2009. View at Publisher · View at Google Scholar · View at Scopus
  27. D. R. Bolster, L. S. Jefferson, and S. R. Kimball, “Regulation of protein synthesis associated with skeletal muscle hypertrophy by insulin, amino acid- and exercise-induced signalling,” Proceedings of the Nutrition Society, vol. 63, no. 2, pp. 351–356, 2004. View at Publisher · View at Google Scholar · View at Scopus
  28. B. S. Kasinath, M. M. Mariappan, K. Sataranatarajan, M. J. Lee, and D. Feliers, “mRNA translation: unexplored territory in renal science,” Journal of the American Society of Nephrology, vol. 17, no. 12, pp. 3281–3292, 2006. View at Publisher · View at Google Scholar · View at Scopus
  29. D. Ruggero and N. Sonenberg, “The Akt of translational control,” Oncogene, vol. 24, no. 50, pp. 7426–7434, 2005. View at Publisher · View at Google Scholar · View at Scopus
  30. L. S. Spruill and P. J. McDermott, “Role of the 5′-untranslated region in regulating translational efficiency of specific mRNAs in adult cardiocytes,” The FASEB Journal, vol. 23, no. 9, pp. 2879–2887, 2009. View at Publisher · View at Google Scholar · View at Scopus
  31. R. A. Frost and C. H. Lang, “mTor signaling in skeletal muscle during sepsis and inflammation: where does it all go wrong?” Physiology, vol. 26, no. 3, pp. 83–96, 2011. View at Google Scholar
  32. B. S. Kasinath, D. Feliers, K. Sataranatarajan, G. G. Choudhury, M. J. Lee, and M. M. Mariappan, “Regulation of mRNA translation in renal physiology and disease,” American Journal of Physiology, vol. 297, no. 5, pp. F1153–F1165, 2009. View at Publisher · View at Google Scholar · View at Scopus
  33. C. G. Proud, “mTORC1 signalling and mRNA translation,” Biochemical Society Transactions, vol. 37, no. 1, pp. 227–231, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. K. Sataranatarajan, M. M. Mariappan, J. L. Myung et al., “Regulation of elongation phase of mRNA translation in diabetic nephropathy: amelioration by rapamycin,” American Journal of Pathology, vol. 171, no. 6, pp. 1733–1742, 2007. View at Publisher · View at Google Scholar · View at Scopus
  35. D. Feliers, S. Duraisamy, J. L. Barnes, G. Ghosh-Choudhury, and B. S. Kasinath, “Translational regulation of vascular endothelial growth factor expression in renal epithelial cells by angiotensin II,” American Journal of Physiology, vol. 288, no. 3, pp. F521–F529, 2005. View at Publisher · View at Google Scholar · View at Scopus
  36. F. M. Boisvert, S. Van Koningsbruggen, J. Navascués, and A. I. Lamond, “The multifunctional nucleolus,” Nature Reviews Molecular Cell Biology, vol. 8, no. 7, pp. 574–585, 2007. View at Publisher · View at Google Scholar · View at Scopus
  37. J. R. Warner, J. Vilardell, and J. H. Sohn, “Economics of ribosome biosynthesis,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 66, pp. 567–574, 2001. View at Google Scholar · View at Scopus
  38. J. D. Lewis and D. Tollervey, “Like attracts like: getting RNA processing together in the nucleus,” Science, vol. 288, no. 5470, pp. 1385–1389, 2000. View at Publisher · View at Google Scholar · View at Scopus
  39. R. Drakas, X. Tu, and R. Baserga, “Control of cell size through phosphorylation of upstream binding factor 1 by nuclear phosphatidylinositol 3-kinase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 25, pp. 9272–9276, 2004. View at Publisher · View at Google Scholar · View at Scopus
  40. A. J. Kihm, J. C. Hershey, T. A. J. Haystead, C. S. Madsen, and G. K. Owens, “Phosphorylation of the rRNA transcription factor upstream binding factor promotes its association with TATA binding protein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 25, pp. 14816–14820, 1998. View at Publisher · View at Google Scholar · View at Scopus
  41. I. Grummt, “Regulation of mammalian ribosomal gene transcription by RNA polymerase I,” Progress in Nucleic acid Research and Molecular Biology, vol. 62, pp. 109–154, 1999. View at Google Scholar · View at Scopus
  42. M. M. Mariappan, K. D'Silva, M. J. Lee et al., “Ribosomal biogenesis induction by high glucose requires activation of upstream binding factor in kidney glomerular epithelial cells,” American Journal of Physiology, vol. 300, no. 1, pp. F219–F230, 2011. View at Publisher · View at Google Scholar
  43. P. Polak and M. N. Hall, “mTOR and the control of whole body metabolism,” Current Opinion in Cell Biology, vol. 21, no. 2, pp. 209–218, 2009. View at Publisher · View at Google Scholar · View at Scopus
  44. S. G. Dann, A. Selvaraj, and G. Thomas, “mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer,” Trends in Molecular Medicine, vol. 13, no. 6, pp. 252–259, 2007. View at Publisher · View at Google Scholar · View at Scopus
  45. M. K. Holz, B. A. Ballif, S. P. Gygi, and J. Blenis, “mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events,” Cell, vol. 123, no. 4, pp. 569–580, 2005. View at Publisher · View at Google Scholar · View at Scopus
  46. A. Yanagiya, Y. V. Svitkin, S. Shibata, S. Mikami, H. Imataka, and N. Sonenberg, “Requirement of RNA binding of mammalian eukaryotic translation initiation factor 4GI (eIF4GI) for efficient interaction of eIF4E with the mRNA cap,” Molecular and Cellular Biology, vol. 29, no. 6, pp. 1661–1669, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. A. C. Gingras, S. G. Kennedy, M. A. O'Leary, N. Sonenberg, and N. Hay, “4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway,” Genes and Development, vol. 12, no. 4, pp. 502–513, 1998. View at Google Scholar · View at Scopus
  48. B. S. Kasinath, M. M. Mariappan, K. Sataranatarajan, M. J. Lee, G. Ghosh Choudhury, and D. Feliers, “Novel mechanisms of protein synthesis in diabetic nephropathy—role of mRNA translation,” Reviews in Endocrine and Metabolic Disorders, vol. 9, no. 4, pp. 255–266, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. N. L. Korneeva, B. J. Lamphear, F. L. C. Hennigan, and R. E. Rhoads, “Mutually cooperative binding of eukaryotic translation initiation factor (eIF) 3 and eIF4A to human eIF4G-1,” The Journal of Biological Chemistry, vol. 275, no. 52, pp. 41369–41376, 2000. View at Publisher · View at Google Scholar · View at Scopus
  50. A. Pause, G. J. Belsham, A. C. Gingras et al., “Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function,” Nature, vol. 371, no. 6500, pp. 762–767, 1994. View at Publisher · View at Google Scholar · View at Scopus
  51. C. G. Proud, “Signalling to translation: how signal transduction pathways control the protein synthetic machinery,” Biochemical Journal, vol. 403, no. 2, pp. 217–234, 2007. View at Publisher · View at Google Scholar · View at Scopus
  52. X. Wang, W. Li, M. Williams, N. Terada, D. R. Alessi, and C. G. Proud, “Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase,” The EMBO Journal, vol. 20, no. 16, pp. 4370–4379, 2001. View at Publisher · View at Google Scholar · View at Scopus
  53. N. T. Redpath, E. J. Foulstone, and C. G. Proud, “Regulation of translation elongation factor-2 by insulin via a rapamycin-sensitive signalling pathway,” The EMBO Journal, vol. 15, no. 9, pp. 2291–2297, 1996. View at Google Scholar · View at Scopus
  54. T. S. Ha, J. L. Barnes, J. L. Stewart et al., “Regulation of renal laminin in mice with type II diabetes,” Journal of the American Society of Nephrology, vol. 10, no. 9, pp. 1931–1939, 1999. View at Google Scholar · View at Scopus
  55. F. N. Ziyadeh, B. B. Hoffman, D. C. Han et al., “Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-β antibody in db/db diabetic mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 14, pp. 8015–8020, 2000. View at Publisher · View at Google Scholar · View at Scopus
  56. D. R. Alessi, L. R. Pearce, and J. M. García-Martínez, “New insights into mTOR signaling: mTORC2 and beyond,” Science Signaling, vol. 2, no. 67, p. pe27, 2009. View at Publisher · View at Google Scholar · View at Scopus
  57. E. Jacinto, V. Facchinetti, D. Liu et al., “SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity,” Cell, vol. 127, no. 1, pp. 125–137, 2006. View at Publisher · View at Google Scholar · View at Scopus
  58. D. D. Sarbassov, D. A. Guertin, S. M. Ali, and D. M. Sabatini, “Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex,” Science, vol. 307, no. 5712, pp. 1098–1101, 2005. View at Publisher · View at Google Scholar · View at Scopus
  59. W. J. Oh, C. C. Wu, S. J. Kim et al., “MTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide,” The EMBO Journal, vol. 29, no. 23, pp. 3939–3951, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. X. Xie and K.-L. Guan, “The ribosome and TORC2: collaborators for cell growth,” Cell, vol. 144, no. 5, pp. 640–642, 2011. View at Publisher · View at Google Scholar
  61. G. Kramer, D. Boehringer, N. Ban, and B. Bukau, “The ribosome as a platform for co-translational processing, folding and targeting of newly synthesized proteins,” Nature Structural and Molecular Biology, vol. 16, no. 6, pp. 589–597, 2009. View at Publisher · View at Google Scholar · View at Scopus
  62. N. Lloberas, J. M. Cruzado, M. Franquesa et al., “Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats,” Journal of the American Society of Nephrology, vol. 17, no. 5, pp. 1395–1404, 2006. View at Publisher · View at Google Scholar · View at Scopus
  63. H. Mori, K. Inoki, K. Masutani et al., “The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential,” Biochemical and Biophysical Research Communications, vol. 384, no. 4, pp. 471–475, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. M. Sakaguchi, M. Isono, K. Isshiki, T. Sugimoto, D. Koya, and A. Kashiwagi, “Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice,” Biochemical and Biophysical Research Communications, vol. 340, no. 1, pp. 296–301, 2006. View at Publisher · View at Google Scholar · View at Scopus
  65. Y. Yang, J. Wang, L. Qin et al., “Rapamycin prevents early steps of the development of diabetic nephropathy in rats,” American Journal of Nephrology, vol. 27, no. 5, pp. 495–502, 2007. View at Publisher · View at Google Scholar · View at Scopus
  66. M. Gödel, B. Hartleben, N. Herbach et al., “Role of mTOR in podocyte function and diabetic nephropathy in humans and mice,” The Journal of Clinical Investigation, vol. 121, no. 6, pp. 2197–2209, 2011. View at Publisher · View at Google Scholar
  67. K. Inoki, H. Mori, J. Wang et al., “mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice,” Journal of Clinical Investigation, vol. 121, no. 6, pp. 2181–2196, 2011. View at Publisher · View at Google Scholar
  68. J. Chen, J. K. Chen, E. G. Neilson, and R. C. Harris, “Role of EGF receptor activation in angiotensin II-induced renal epithelial cell hypertrophy,” Journal of the American Society of Nephrology, vol. 17, no. 6, pp. 1615–1623, 2006. View at Publisher · View at Google Scholar · View at Scopus
  69. M. M. Mariappan, D. Senthil, K. S. Natarajan, G. G. Choudhury, and B. S. Kasinath, “Phospholipase Cγ-Erk axis in vascular endothelial growth factor-induced eukaryotic initiation factor 4E phosphorylation and protein synthesis in renal epithelial cells,” The Journal of Biological Chemistry, vol. 280, no. 31, pp. 28402–28411, 2005. View at Publisher · View at Google Scholar · View at Scopus
  70. D. F. Ding, N. You, X. M. Wu et al., “Resveratrol attenuates renal hypertrophy in early-stage diabetes by activating AMPK,” American Journal of Nephrology, vol. 31, no. 4, pp. 363–374, 2010. View at Publisher · View at Google Scholar · View at Scopus
  71. M. J. Lee, D. Feliers, K. Sataranatarajan et al., “Resveratrol ameliorates high glucose-induced protein synthesis in glomerular epithelial cells,” Cellular Signalling, vol. 22, no. 1, pp. 65–70, 2010. View at Publisher · View at Google Scholar · View at Scopus
  72. M. Ravid, D. Brosh, Z. Levi, Y. Bar-Dayan, D. Ravid, and R. Rachmani, “Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus: a randomized, controlled trial,” Annals of Internal Medicine, vol. 128, no. 12, pp. 982–988, 1998. View at Google Scholar · View at Scopus
  73. A. Y. M. Chan, C. L. M. Soltys, M. E. Young, C. G. Proud, and J. R. B. Dyck, “Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte,” The Journal of Biological Chemistry, vol. 279, no. 31, pp. 32771–32779, 2004. View at Publisher · View at Google Scholar · View at Scopus
  74. D. R. Vyas, E. E. Spangenburg, T. W. Abraha, T. E. Childs, and F. W. Booth, “GSK-3β negatively regulates skeletal myotube hypertrophy,” American Journal of Physiology, vol. 283, no. 2, pp. C545–C551, 2002. View at Google Scholar · View at Scopus
  75. S. Haq, G. Choukroun, Z. B. Kang et al., “Glycogen synthase kinase-3β is a negative regulator of cardiomyocyte hypertrophy,” Journal of Cell Biology, vol. 151, no. 1, pp. 117–129, 2000. View at Publisher · View at Google Scholar · View at Scopus
  76. S. E. Hardt and J. Sadoshima, “Glycogen synthase kinase-3β a novel regulator of cardiac hypertrophy and development,” Circulation Research, vol. 90, no. 10, pp. 1055–1063, 2002. View at Publisher · View at Google Scholar · View at Scopus
  77. H. Deng, M. B. Hershenson, J. Lei, A. C. Anyanwu, D. J. Pinsky, and J. Kelley Bentley, “Pulmonary artery smooth muscle hypertrophy: roles of glycogen synthase kinase-3β and p70 ribosomal S6 kinase,” American Journal of Physiology, vol. 298, no. 6, pp. L793–L803, 2010. View at Publisher · View at Google Scholar · View at Scopus
  78. G. I. Welsh, C. M. Miller, A. J. Loughlin, N. T. Price, and C. G. Proud, “Regulation of eukaryotic initiation factor eIF2B: Glycogen synthase kinase-3 phosphorylates a conserved serine which undergoes dephosphorylation in response to insulin,” FEBS Letters, vol. 421, no. 2, pp. 125–130, 1998. View at Publisher · View at Google Scholar
  79. T. Preiss and M. W. Hentze, “Starting the protein synthesis machine: Eukaryotic translation initiation,” BioEssays, vol. 25, no. 12, pp. 1201–1211, 2003. View at Publisher · View at Google Scholar
  80. M. M. Mariappan, M. Shetty, K. Sataranatarajan, G. G. Choudhury, and B. S. Kasinath, “Glycogen synthase kinase 3β is a novel regulator of high glucose- and high insulin-induced extracellular matrix protein synthesis in renal proximal tubular epithelial cells,” The Journal of Biological Chemistry, vol. 283, no. 45, pp. 30566–30575, 2008. View at Publisher · View at Google Scholar · View at Scopus
  81. C. L. Antos, T. A. McKinsey, N. Frey et al., “Activated glycogen synthase-3β suppresses cardiac hypertrophy in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 2, pp. 907–912, 2002. View at Publisher · View at Google Scholar · View at Scopus
  82. K. M. Boini, K. Amann, D. Kempe, D. R. Alessi, and F. Lang, “Proteinuria in mice expressing PKB/SGK-resistant GSK3,” American Journal of Physiology, vol. 296, no. 1, pp. F153–F159, 2009. View at Publisher · View at Google Scholar · View at Scopus
  83. C. G. Proud, “Dynamic balancing: DEPTOR tips the scales,” Journal of Molecular Cell Biology, vol. 1, no. 2, pp. 61–63, 2009. View at Google Scholar · View at Scopus
  84. R. Zoncu, A. Efeyan, and D. M. Sabatini, “MTOR: from growth signal integration to cancer, diabetes and ageing,” Nature Reviews Molecular Cell Biology, vol. 12, no. 1, pp. 21–35, 2011. View at Publisher · View at Google Scholar · View at Scopus
  85. T. R. Peterson, M. Laplante, C. C. Thoreen et al., “DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival,” Cell, vol. 137, no. 5, pp. 873–886, 2009. View at Publisher · View at Google Scholar · View at Scopus
  86. M. Liu, S. A. Wilk, A. Wang et al., “Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR,” The Journal of Biological Chemistry, vol. 285, no. 47, pp. 36387–36394, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. A. A. Kazi, L. Hong-Brown, S. M. Lang, and C. H. Lang, “Deptor knockdown enhances mTOR activity and protein synthesis in myocytes and ameliorates disuse muscle atrophy,” Molecular Medicine, vol. 17, no. 9-10, pp. 925–936, 2011. View at Google Scholar
  88. Y. Sun, S. Koo, N. White et al., “Development of a micro-array to detect human and mouse microRNAs and characterization of expression in human organs,” Nucleic Acids Research, vol. 32, no. 22, article e188, 2004. View at Google Scholar · View at Scopus
  89. M. Kato, L. Arce, M. Wang, S. Putta, L. Lanting, and R. Natarajan, “A microRNA circuit mediates transforming growth factor-beta1 autoregulation in renal glomerular mesangial cells,” Kidney International, vol. 80, no. 4, pp. 358–368, 2011. View at Publisher · View at Google Scholar
  90. M. Kato, J. Zhang, M. Wang et al., “MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-β-induced collagen expression via inhibition of E-box repressors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 9, pp. 3432–3437, 2007. View at Publisher · View at Google Scholar · View at Scopus
  91. Q. Wang, Y. Wang, A. W. Minto et al., “MicroRNA-377 is up-regulated and can lead to increased fibronectin production in diabetic nephropathy,” The FASEB Journal, vol. 22, no. 12, pp. 4126–4135, 2008. View at Publisher · View at Google Scholar · View at Scopus
  92. J. Long, Y. Wang, W. Wang, B. H. J. Chang, and F. R. Danesh, “MicroRNA-29c is a signature MicroRNA under high glucose conditions that targets sprouty homolog 1, and its in vivo knockdown prevents progression of diabetic nephropathy,” The Journal of Biological Chemistry, vol. 286, no. 13, pp. 11837–11848, 2011. View at Publisher · View at Google Scholar
  93. M. Selbach, B. Schwanhäusser, N. Thierfelder, Z. Fang, R. Khanin, and N. Rajewsky, “Widespread changes in protein synthesis induced by microRNAs,” Nature, vol. 455, no. 7209, pp. 58–63, 2008. View at Publisher · View at Google Scholar · View at Scopus
  94. I. Behm-Ansmant, J. Rehwinkel, and E. Izaurralde, “MicroRNAs silence gene expression by repressing protein expression and/or by promoting mRNA decay,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 71, pp. 523–530, 2006. View at Publisher · View at Google Scholar · View at Scopus
  95. J. G. Doench and P. A. Sharp, “Specificity of microRNA target selection in translational repression,” Genes and Development, vol. 18, no. 5, pp. 504–511, 2004. View at Publisher · View at Google Scholar · View at Scopus
  96. N. Dey, F. Das, M. M. Mariappan et al., “MicroRNA-21 orchestrates high glucose-induced signals to TOR complex 1, resulting in renal cell pathology in diabetes,” The Journal of Biological Chemistry, vol. 286, no. 29, pp. 25586–25603, 2011. View at Publisher · View at Google Scholar
  97. B. S. Kasinath and D. Feliers, “The complex world of kidney microRNAs,” Kidney International, vol. 80, no. 4, pp. 334–337, 2011. View at Publisher · View at Google Scholar
  98. M. A. Reddy and R. Natarajan, “Epigenetic mechanisms in diabetic vascular complications,” Cardiovascular Research, vol. 90, no. 3, pp. 421–429, 2011. View at Publisher · View at Google Scholar
  99. M. E. Cooper and A. El-Osta, “Epigenetics: mechanisms and implications for diabetic complications,” Circulation Research, vol. 107, no. 12, pp. 1403–1413, 2010. View at Publisher · View at Google Scholar · View at Scopus
  100. S. Tonna, A. El-Osta, M. E. Cooper, and C. Tikellis, “Metabolic memory and diabetic nephropathy: potential role for epigenetic mechanisms,” Nature Reviews Nephrology, vol. 6, no. 6, pp. 332–341, 2010. View at Publisher · View at Google Scholar · View at Scopus
  101. L. M. Villeneuve, M. A. Reddy, and R. Natarajan, “Epigenetics: deciphering its role in diabetes and its chronic complications,” Clinical and Experimental Pharmacology and Physiology, vol. 38, no. 7, pp. 401–409, 2011. View at Publisher · View at Google Scholar
  102. T. J. Allen, M. E. Cooper, and H. Y. Lan, “Use of genetic mouse models in the study of diabetic nephropathy,” Current Atherosclerosis Reports, vol. 6, no. 3, pp. 197–202, 2004. View at Google Scholar · View at Scopus
  103. K. Srinivasan and P. Ramarao, “Animal models in type 2 diabetes research: an overview,” Indian Journal of Medical Research, vol. 125, no. 3, pp. 451–472, 2007. View at Google Scholar · View at Scopus
  104. M. P. Cohen, R. S. Clements, E. Hud, J. A. Cohen, and F. N. Ziyadeh, “Evolution of renal function abnormalities in the db/db mouse that parallels the development of human diabetic nephropathy,” Experimental Nephrology, vol. 4, no. 3, pp. 166–171, 1996. View at Google Scholar · View at Scopus
  105. D. Feliers, S. Duraisamy, J. L. Faulkner et al., “Activation of renal signaling pathways in db/db mice with type 2 diabetes,” Kidney International, vol. 60, no. 2, pp. 495–504, 2001. View at Publisher · View at Google Scholar · View at Scopus
  106. L. M. Chen, X. W. Li, L. W. Huang, Y. Li, L. Duan, and X. J. Zhang, “The early pathological changes of KKAy mice with type 2 diabetes,” Acta Academiae Medicinae Sinicae, vol. 24, no. 1, pp. 71–75, 2002. View at Google Scholar · View at Scopus
  107. S. Hagiwara, Y. Makita, L. Gu et al., “Eicosapentaenoic acid ameliorates diabetic nephropathy of type 2 diabetic KKAy/Ta mice: involvement of MCP-1 suppression and decreased ERK1/2 and p38 phosphorylation,” Nephrology Dialysis Transplantation, vol. 21, no. 3, pp. 605–615, 2006. View at Publisher · View at Google Scholar · View at Scopus
  108. M. Okazaki, Y. Saito, Y. Udaka et al., “Diabetic nephropathy in KK and KK-Ay mice,” Experimental Animals, vol. 51, no. 2, pp. 191–196, 2002. View at Publisher · View at Google Scholar · View at Scopus
  109. C.-H. Kim, P. Pennisi, H. Zhao et al., “MKR mice are resistant to the metabolic actions of both insulin and adiponectin: discordance between insulin resistance and adiponectin responsiveness,” American Journal of Physiology, vol. 291, no. 2, pp. E298–E305, 2006. View at Publisher · View at Google Scholar
  110. A. M. Fernández, J. K. Kim, S. Yakar et al., “Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes,” Genes and Development, vol. 15, no. 15, pp. 1926–1934, 2001. View at Publisher · View at Google Scholar · View at Scopus
  111. M. Mauer, B. Zinman, R. Gardiner et al., “ACE-I and ARBs in early diabetic nephropathy,” JRAAS, vol. 3, no. 4, pp. 262–269, 2002. View at Google Scholar · View at Scopus
  112. L. K. Davis, B. D. Rodgers, and K. M. Kelley, “Angiotensin II- and glucose-stimulated extracellular matrix production: mediation by the insulin-like growth factor (IGF) axis in a murine mesangial cell line,” Endocrine, vol. 33, no. 1, pp. 32–39, 2008. View at Publisher · View at Google Scholar · View at Scopus
  113. K. Sharma, J. H. Ix, A. V. Mathew et al., “Pirfenidone for diabetic nephropathy,” Journal of the American Society of Nephrology, vol. 22, no. 6, pp. 1144–1151, 2011. View at Publisher · View at Google Scholar
  114. N. Nakao, A. Yoshimura, H. Morita, M. Takada, T. Kayano, and T. Ideura, “Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial,” The Lancet, vol. 361, no. 9352, pp. 117–124, 2003. View at Publisher · View at Google Scholar · View at Scopus
  115. M. C. Thomas and P.-H. Groop, “New approaches to the treatment of nephropathy in diabetes,” Expert Opinion on Investigational Drugs, vol. 20, no. 8, pp. 1057–1071, 2011. View at Publisher · View at Google Scholar