Thiazolidinediones and Edema: Recent Advances in the Pathogenesis of Thiazolidinediones-Induced Renal Sodium Retention

Horita, Shoko; Nakamura, Motonobu; Satoh, Nobuhiko; Suzuki, Masashi; Seki, George

doi:https://doi.org/10.1155/2015/646423

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Volume 2015 | Article ID 646423 | https://doi.org/10.1155/2015/646423

Thiazolidinediones and Edema: Recent Advances in the Pathogenesis of Thiazolidinediones-Induced Renal Sodium Retention

Shoko Horita,¹Motonobu Nakamura,¹Nobuhiko Satoh,¹Masashi Suzuki,¹and George Seki¹

Academic Editor: Tianxin Yang

Received09 Feb 2015

Accepted03 May 2015

Published14 May 2015

Abstract

Thiazolidinediones (TZDs) are one of the major classes of antidiabetic drugs that are used widely. TZDs improve insulin resistance by activating peroxisome proliferator-activated receptor gamma (PPARγ) and ameliorate diabetic and other nephropathies, at least, in experimental animals. However, TZDs have side effects, such as edema, congestive heart failure, and bone fracture, and may increase bladder cancer risk. Edema and heart failure, which both probably originate from renal sodium retention, are of great importance because these side effects make it difficult to continue the use of TZDs. However, the pathogenesis of edema remains a matter of controversy. Initially, upregulation of the epithelial sodium channel (ENaC) in the collecting ducts by TZDs was thought to be the primary cause of edema. However, the results of other studies do not support this view. Recent data suggest the involvement of transporters in the proximal tubule, such as sodium-bicarbonate cotransporter and sodium-proton exchanger. Other studies have suggested that sodium-potassium-chloride cotransporter 2 in the thick ascending limb of Henle and aquaporins are also possible targets for TZDs. This paper will discuss the recent advances in the pathogenesis of TZD-induced sodium reabsorption in the renal tubules and edema.

1. The Target of Thiazolidinediones: Peroxisome Proliferator-Activated Receptor Gamma (PPARγ)

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily of ligand-inducible transcription factors [1], involved in lipid metabolism and energy homeostasis [2]. In mammals, three PPAR subtypes, PPARα, PPARβ/δ, and PPARγ, are known to exist. PPARs bind to PPAR-responsive regulatory elements (PRREs) in combination with retinoid X receptor (RXR) and control the expression of genes engaged in several biological processes, such as lipid metabolism, adipogenesis, inflammation, and maintenance of metabolic homeostasis [3]. PPARs consist of an N-terminal transactivation domain, which is quite diverse and contains the AF1, a DNA-binding domain (DBD), which is highly conserved, and a ligand-binding domain (LBD) in the C-terminal, which contains the AF2 [4].

PPARγ has two isoforms, PPARγ1 and PPARγ2 [5, 6]. PPARγ2 is longer than PPARγ1, with an extra 30 amino acids at its N-terminus. PPARγ1 is expressed in a wide range of tissue types, which include white and brown adipose tissue, cardiac muscle, and liver tissue, whereas PPARγ2 is expressed almost exclusively in adipose tissue [7, 8]. However, the expression of PPARγ2 is induced in other tissues by a high fat diet [9].

PPARγ is a key regulator of adipogenesis [1, 10]. It is expressed abundantly in white and brown adipocytes and plays important roles in regulating lipid metabolism and insulin sensitivity. Additionally, PPARγ functions as a multipotent modulator of inflammation, gluconeogenesis, and fluid homeostasis.

Disruption of the PPARγ gene in mice yielded intriguing results [11]. Homozygous PPARγ deficiency led to embryonic lethality due to placental dysfunction. Embryonic fibroblasts from PPAR mice failed to differentiate into adipocytes, suggesting that PPARγ is essential for the differentiation of embryonic fibroblasts into adipocytes. On the other hand, heterozygous PPAR mice gained little weight under a high-fat diet. Moreover, the PPAR mice had higher sensitivity to endogenous insulin than wild-type mice. PPARγ may have dual roles in regulating insulin resistance, at least in experimental mice.

2. PPARγ and Kidney

In the kidney, PPARγ is mainly expressed in the collecting ducts. However, some studies have shown that PPARγ is also expressed in other nephron segments, such as the proximal tubule (PT) and distal tubule, as well as glomeruli, podocytes, and mesangial cells [12, 19–23]. PPARγ is speculated to have renoprotective effects. For example, PPARγ seems to attenuate podocyte damage. Kanjanabuch et al. showed that PPARγ agonists prevented podocyte injury [24]. Additionally, they showed that TZDs increased PPARγ expression and activity in cultured puromycin-injured mouse podocytes [24]. Other studies have shown that although PPARγ agonist treatment cannot rescue renal function, it does raise adiponectin levels in mice [25]. As adiponectin improves podocyte recovery [25], PPARγ, together with adiponectin, may have some protective roles in podocytes.

The activation of PPARγ by TZDs seems to protect mesangial cells from the development of diabetic change via the inhibition of inflammatory cascades [26] or TGF-β signaling cascades [27]. The activation of glomerular PPARγ may have potential for the treatment of diabetic nephropathy. However, the detailed mechanism by which PPARγ exerts its protective effects on the kidney as a whole remains to be clarified.

3. Thiazolidinediones (TZDs): Multipotent Roles in Glucose Metabolism

Thiazolidinediones (TZDs) were first discovered as insulin-sensitizing drugs [28]. In 1995, they were found to enact their pharmacological effects by binding to and activating PPARγ [29, 30]. TZDs act as agonists for PPARγ and ameliorate insulin sensitivity in the liver, muscle, and adipocytes [31–35]. There are several views on the manner in which TZDs enhance insulin sensitivity. One view is that TZDs enhance insulin signaling by stimulating insulin receptor substrate 1 (IRS-1) and inhibiting the MAPK pathway [34]. Another is that TZDs act in adipose tissue to increase adiponectin secretion while inhibiting lipolysis [2, 31] and the release of inflammatory cytokines, such as transforming growth factor-β (TGF-β). Recently Spiegelman and colleagues proposed that TZDs inhibit the phosphorylation of PPARγ at Ser273 by cyclin-dependent kinase (Cdk) 5, thus preventing the development of insulin resistance [36]. They also suggested that the phosphorylation of PPARγ is blocked by the inhibition of MEK/ERK. In this study, Cdk5 was shown to suppress the MEK/ERK cascade, which suggests that Cdk5 controls PPARγ function [37].

In some animal models of diabetic nephropathy, such as Zucker diabetic fatty rats and Wister fatty rats, TZDs have been shown to reduce mesangial matrix volume, decrease proteinuria, and prevent the aggravation of renal function [38, 39]. TZDs have also been shown to inhibit the mRNA expression of cell matrix proteins (e.g., collagen and fibronectin) and TGF-β in mouse mesangial primary culture cells [27], pregnant diabetic rat models [40], and a mouse mesangial cell line [41], which indicates that TZDs inhibit mesangial cell proliferation. These results suggest that TZDs indirectly protect glomeruli against diabetic changes. Moreover, TZDs have been reported to have other renoprotective effects, such as the lowering of blood pressure, blood glucose, and insulin levels and the reduction of microalbuminuria in experimental animals, such as obese Zucker rats, streptozotocin-induced diabetic rats, and a rat model of partial nephrectomy [42, 43]. However, TZDs do not seem to reduce marcoalbuminuria in humans [43].

Also in humans, TZDs have been suggested to improve glucose homeostasis, lower blood pressure, and reduce microalbuminuria, unlike other antidiabetic drugs, such as insulin, sulfonylureas, and α-glucosidase inhibitors [44, 45]. Recently, TZDs were shown to prevent the onset of diabetes mellitus (DM) in persons with impaired glucose tolerance in a randomized, double-blind, and placebo-controlled clinical study [46]. On the other hand, some studies have shown that the decrease in urinary albumin-creatinine ratio after TZD treatment was comparable to that observed after gliclazide [47] and insulin [48] treatment. The above data show that treatment with TZDs can reduce microalbuminuria and may prevent the onset of DM. However, currently no studies have shown that TZDs can prevent the development and progression of human chronic kidney disease.

4. The Side Effects of TZDs

TZDs have many beneficial effects, including preventing the emergence and progression of DM and hypertension and their complications and preventing vicious phenomena, such as endothelial-mesenchymal transition (EMT), inflammatory responses, and fibrosis [46]. However, TZDs also have some important side effects [49]. Troglitazone has been withdrawn from the market because it was found to cause fatal liver dysfunction. Clinically, renal sodium retention and congestive heart failure (CHF) are probably the most important and troublesome side effects of TZDs. Plasma volume expansion and cardiac failure make the treatment of DM complicated [50]. Additionally, cardiovascular risks and concerns of TZDs raising mortality by causing CHF have been presented [51, 52].

TZDs also seem to increase vascular permeability in several tissues, which contributes to producing peripheral edema. Rosiglitazone was shown to enhance vascular permeability selectively in adipose tissues and retina, but not in muscle [53]. Vascular endothelial growth factor (VEGF) may be responsible for the increment of vascular permeability in the adipocytes [54].

TZDs might also cause bone fracture. Rosiglitazone is suggested to decrease bone mineral density and increase bone turnover in menopausal women; however, further investigations are required to clarify the mechanism of this effect of rosiglitazone [55–57]. At present, the most important matter of controversy regarding TZDs is probably the possibility that pioglitazone can cause bladder cancer [58, 59].

5. TZDs and Congestive Heart Failure (CHF)

Sodium retention accompanied with the use of TZDs sometimes makes the continuous use of TZDs difficult or impossible due to severe CHF. Approximately 5% of patients using TZDs develop peripheral edema. However, when used with other antidiabetic drugs, the risk of peripheral edema increases to approximately 18% [60]. Additionally, the risk of edema caused when 8 mg rosiglitazone is taken with insulin is 16.2%, compared to 4.7% for insulin alone [61]. However, TZDs are not thought to worsen cardiac function by themselves [62]. In the PROactive 05 study, pioglitazone treatment resulted in 28% reduction of fatal and nonfatal myocardial infarctions and 37% reduction of acute coronary syndromes compared to placebo [63]. CHF induced by TZD administration is thought to be due to renal sodium retention. At present, TZDs do not seem to increase mortality due to CHF [64]; however, there are some counterarguments regarding this point, as described above [51, 52]. According to the American Diabetes Association and the American Heart Association recommendation, patients suffering from NYHA class III or IV CHF should not take TZDs [60, 65].

6. The Mechanism of TZD-Induced Renal Sodium and Water Retention

As mentioned above, edema and CHF caused by TZDs are great issues clinically. In Sprague-Dawley rat models, Song et al. first showed that renal sodium retention due to an increase of tubular transporters and a decrease in glomerular filtration rate is the main cause of volume expansion by TZDs [13]. However, the detailed molecular mechanism of renal sodium retention by the kidney is still in dispute. At first, the epithelial sodium channel (ENaC) was thought to be the main cause of this volume expansion. Guan and colleagues reported that mice treated with TZDs showed weight gain which was blocked by amiloride. On the contrary, in AQP2-Cre x Ppar mice, with selective deletion of Pparg from the collecting duct, TZDs did not cause volume expansion. In primary culture of IMCD cells from AQP2-Cre x Ppar mice, pioglitazone failed to enhance amiloride-sensitive sodium transport, but it significantly enhanced amiloride-sensitive sodium transport in control IMCD cells. Additionally, as in mouse IMCD cells, pioglitazone treatment increased Scnn1g mRNA, suggesting that pioglitazone enhanced ENaC-γ subunit expression [14].

Zhang and colleagues [15] also showed that mice with collecting duct-specific knockout of the PPARγ gene were resistant to TZD-induced weight gain and plasma volume expansion. In primary cultured collecting tubule cells of mice expressing PPARγ, TZDs enhanced sodium transport. However, in cells lacking PPARγ, TZDs did not enhance sodium transport. These two works suggest that TZDs induce plasma volume expansion by increasing sodium transport via ENaC in the cortical collecting duct (CCD). In particular, PPARγ was thought to mediate the enhancement of the expression of the ENaC-γ subunit. Moreover, another study [66] suggested that serum glucocorticoid regulated kinase 1 (SGK1) mediates the stimulatory effect of TZDs on ENaC.

However, other studies did not support the conclusion that TZDs enhance sodium transport via the activation of ENaC in the CCD. In well-established cell lines, such as A6, M-1, and mpkCC, insulin is known to stimulate ENaC activity. However, in these cells, TZDs failed to directly augment basal or insulin-stimulated N flux via ENaC [18]. This clearly contradicts the view that TZDs enhance ENaC activity via PPARγ regulation. Additionally, in the kidneys of Sprague-Dawley rats, TZDs failed to upregulate the expression of any ENaC subunit [13]. Vallon and colleagues showed that mice with conditionally inactivated ENaCα in the collecting duct showed almost the same level of fluid retention after TZD treatment as control mice. In patch clamp studies using primary cultured collecting duct cells, a nonselective cation channel, not ENaC, was activated by TZDs. They also showed that TZDs repress ENaC activity in mice, both in the acute phase (several hours) and chronic phase (days) [16, 17]. Moreover, others showed that TZDs did not enhance the ENaC promoter [17]. These results certainly argue against the view that TZDs enhance ENaC in the CCD.

Some studies have suggested that renal PT transport is stimulated by TZDs, both in animals [67] and humans [68]. Based on these observations, we speculate that TZD-induced volume expansion is multifactorial and that PT could be another target segment for TZDs. Furthermore, the “aldosterone escape” phenomenon should be considered: even if aldosterone enhances ENaC activity in the collecting duct, it suppresses sodium reabsorption in other nephron segments. Therefore ENaC activation by aldosterone excess alone does not usually induce massive volume expansion with edema formation [69].

We found [12] that TZDs markedly stimulate bicarbonate-coupled sodium transport in isolated PTs of rabbits, rats, and humans. TZDs activated both a sodium-bicarbonate cotransporter (NBCe1) and a sodium/proton exchanger (NHE3) through the PPARγ/Src/EGFR/ERK pathway. However, in mice, TZDs failed to stimulate PT transport both in vivo and in vitro. This is consistent with a previous report that showed that Src/EGFR/ERK is constitutively activated in mice [70].

TZDs trigger various rapid cellular signaling events, including the activation of kinase signaling pathways, such as phosphatidylinositol 3-kinase (PI3K), Akt, ERK, and MAPK pathways, in a nongenomic manner [71]. We transfected mouse embryonic fibroblast cells from PPAR mouse with the ligand binding domain of PPARγ. This experiment confirmed the presence of nongenomic signaling that resulted in the activation of ERK; this signal required PPARγ to have ligand-binding ability but did not require the transcription of PPARγ [12]. Additionally we showed that TZDs rapidly facilitate the association of PPARγ with Src, which is also dependent on the ligand-binding ability of PPARγ. These results, together with the rapid kinetics of responses that are independent of transcriptional activity, indicate that PPARγ can activate the ERK pathway through nongenomic mechanism, similar to another nuclear receptor, estrogen [72]. The dependence on Src, the association between PPARγ and Src, and the negative effect of constitutive Src activation in PPARγ-dependent nongenomic signaling support the central role of Src in this signaling pathway. The magnitude of the enhancement of PT transport by TZDs is comparable to, or even exceeds, that of angiotensin II [73]. In PT, angiotensin II is thought to be the strongest stimulatory hormone. Therefore, we concluded that the stimulation of renal PT transport via PPARγ-dependent, nongenomic signaling may play an important role in the plasma volume expansion induced by TZDs [12].

Other channels/transporters have also been suggested to be regulated by PPARγ and its agonists, TZDs. The expression level of aquaporin 3 (AQP3) mRNA in the renal outer medulla was stronger in TZD-treated Otsuka Long-Evans Tokushima Fatty (OLETF) rats than in OLETF rats without TZD treatment and control LETO rats [74]. Another study showed that TZD treatment increased the expression of AQP3 protein in diabetic db/db mice but not in wild-type mice. Another aquaporin, AQP2, was downregulated in lean wild-type mice but not in db/db mice [75]. Aquaporins have 13 subtypes, and many of them are expressed widely in nephron segments and are mainly involved in water transport [76, 77]. In particular, AQP2 is located in CCD and is known as a target for vasopressin [78]. AQP3 is located in the basolateral side of the collecting duct and is involved in water reabsorption [79]. Additionally, in the kidney of Sprague-Dawley rats, the protein expression of NHE3 and NKCC2 was elevated after TZD treatment [13]. NKCC2 reabsorbs sodium and potassium coupled with chloride, predominantly in the apical side of the thick ascending limb of Henle (TAL) [80, 81]. These results strongly suggest that the volume expanding effect of TZDs is multifactorial. Recently Fu and colleagues have reported that ENaC in the connecting tubule may play a role in the fluid retention induced by TZD [82]. Table 1 summarizes the potential targets of TZDs in the PT and TAL. The controversial data as to the potential effects of TZDs on ENaC are summarized in Table 2.

The development of new TZDs with less side effects seems to be difficult. Rivoglitazone was not released because its effects and side effects were not significantly different from those of pioglitazone [83]. A selective PPARγ activator with less frequency of edema, INT131, is now being examined by a clinical trial [84]. Such drugs may help in the therapy of DM in the near future.

7. Conclusions

We have overviewed PPARγ, its agonists, TZDs, and their side effects with a focus on the mechanisms of edema and sodium retention. TZDs are highly effective antidiabetic drugs with unique functions, such as a renoprotective effect, amelioration of glucose homeostasis, and blood pressure lowering, that other antidiabetic drugs do not have. However, the use of TZDs is often associated with edema and CHF, which make it impossible to use TZDs in case of severe CHF. The mechanism by which TZDs induce volume expansion may be multifactorial, as shown in Table 1. At first ENaC in the CCD was thought to play a central role in TZD-induced volume expansion; however, the results of other studies have not supported this view and suggested the involvement of other transporters in the CCD. We have found that NBCe1 and/or NHE3 in the PT may play a significant role in TZD-induced sodium retention through a PPARγ-dependent nongenomic mechanism. Other sodium and water transporters, such as NKCC2, AQP2, and AQP3, have also been proposed as targets for TZDs. The development of novel TZDs or PPARγ modulators with less side effects is expected.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

R. M. Evans, G. D. Barish, and Y. Wang, “PPARs and the complex journey to obesity,” Nature Medicine, vol. 10, no. 4, pp. 355–361, 2004.
View at: Publisher Site | Google Scholar
R. Eldor, R. A. DeFronzo, and M. Abdul-Ghani, “In vivo actions of peroxisome proliferator-activated receptors: glycemic control, insulin sensitivity, and insulin secretion,” Diabetes Care, vol. 36, no. 2, pp. S162–S174, 2013.
View at: Publisher Site | Google Scholar
M. Ahmadian, J. M. Suh, N. Hah et al., “PPARγ signaling and metabolism: the good, the bad and the future,” Nature Medicine, vol. 19, no. 5, pp. 557–566, 2013.
View at: Publisher Site | Google Scholar
C. Helsen and F. Claessens, “Looking at nuclear receptors from a new angle,” Molecular and Cellular Endocrinology, vol. 382, no. 1, pp. 97–106, 2014.
View at: Publisher Site | Google Scholar
A. Elbrecht, Y. Chen, C. A. Cullinan et al., “Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors $γ$ 1 and $γ$ 2,” Biochemical and Biophysical Research Communications, vol. 224, no. 2, pp. 431–437, 1996.
View at: Publisher Site | Google Scholar
M. E. Greene, B. Blumberg, O. W. McBride et al., “isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping,” Gene Expression, vol. 4, no. 4-5, pp. 281–299, 1995.
View at: Google Scholar
A. J. Vidal-Puig, R. V. Considine, M. Jimenez-Liñan et al., “Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids,” The Journal of Clinical Investigation, vol. 99, no. 10, pp. 2416–2422, 1997.
View at: Publisher Site | Google Scholar
P. Tontonoz, R. A. Graves, A. I. Budavari et al., “Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPARγ and RXRα,” Nucleic Acids Research, vol. 22, no. 25, pp. 5628–5634, 1994.
View at: Publisher Site | Google Scholar
G. Medina-Gomez, S. L. Gray, L. Yetukuri et al., “PPAR gamma 2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism,” PLoS Genetics, vol. 3, no. 4, p. e64, 2007.
View at: Publisher Site | Google Scholar
P. Tontonoz and B. M. Spiegelman, “Fat and beyond: the diverse biology of PPARγ,” Annual Review of Biochemistry, vol. 77, pp. 289–312, 2008.
View at: Publisher Site | Google Scholar
N. Kubota, Y. Terauchi, H. Miki et al., “PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance,” Molecular Cell, vol. 4, no. 4, pp. 597–609, 1999.
View at: Publisher Site | Google Scholar
Y. Endo, M. Suzuki, H. Yamada et al., “Thiazolidinediones enhance sodium-coupled bicarbonate absorption from renal proximal tubules via PPARγ-dependent nongenomic signaling,” Cell Metabolism, vol. 13, no. 5, pp. 550–561, 2011.
View at: Publisher Site | Google Scholar
J. Song, M. A. Knepper, X. Hu, J. G. Verbalis, and C. A. Ecelbarger, “Rosiglitazone activates renal sodium- and water-reabsorptive pathways and lowers blood pressure in normal rats,” The Journal of Pharmacology and Experimental Therapeutics, vol. 308, no. 2, pp. 426–433, 2004.
View at: Publisher Site | Google Scholar
Y. Guan, C. Hao, D. R. Cha et al., “Thiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC-mediated renal salt absorption,” Nature Medicine, vol. 11, no. 8, pp. 861–866, 2005.
View at: Publisher Site | Google Scholar
H. Zhang, A. Zhang, D. E. Kohan, R. D. Nelson, F. J. Gonzalez, and T. Yang, “Collecting duct-specific deletion of peroxisome proliferator-activated receptor gamma blocks thiazolidinedione-induced fluid retention,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 26, pp. 9406–9411, 2005.
View at: Publisher Site | Google Scholar
V. Vallon, E. Hummler, T. Rieg et al., “Thiazolidinedione-induced fluid retention is independent of collecting duct αENaC activity,” Journal of the American Society of Nephrology, vol. 20, no. 4, pp. 721–729, 2009.
View at: Publisher Site | Google Scholar
E. Borsting, V. P.-C. Cheng, C. K. Glass, V. Vallon, and R. Cunard, “Peroxisome proliferator-activated receptor-γ agonists repress epithelial sodium channel expression in the kidney,” The American Journal of Physiology—Renal Physiology, vol. 302, no. 5, pp. F540–F551, 2012.
View at: Publisher Site | Google Scholar
C. Nofziger, L. Chen, M. A. Shane, C. D. Smith, K. K. Brown, and B. L. Blazer-Yost, “PPAR $γ$ agonists do not directly enhance basal or insulin-stimulated Na⁺ transport via the epithelial Na⁺ channel,” Pflugers Archiv, vol. 451, no. 3, pp. 445–453, 2005.
View at: Publisher Site | Google Scholar
Y. Iwashima, M. Eto, S. Horiuchi, and H. Sano, “Advanced glycation end product-induced peroxisome proliferator-activated receptor γ gene expression in the cultured mesangial cells,” Biochemical and Biophysical Research Communications, vol. 264, no. 2, pp. 441–448, 1999.
View at: Publisher Site | Google Scholar
T. Asano, M. Wakisaka, M. Yoshinari et al., “Peroxisome proliferator-activated receptor γ1 (PPARγ1) expresses in rat mesangial cells and PPARγ agonists modulate its differentiation,” Biochimica et Biophysica Acta, vol. 1497, no. 1, pp. 148–154, 2000.
View at: Publisher Site | Google Scholar
H. Mudaliar, C. Pollock, M. G. Komala, S. Chadban, H. Wu, and U. Panchapakesan, “The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules,” American Journal of Physiology—Renal Physiology, vol. 305, no. 2, pp. F143–F154, 2013.
View at: Publisher Site | Google Scholar
Y. Guan, Y. Zhang, L. Davis, and M. D. Breyer, “Expression of peroxisome proliferator-activated receptors in urinary tract of rabbits and humans,” American Journal of Physiology—Renal Physiology, vol. 273, no. 6, pp. F1013–F1022, 1997.
View at: Google Scholar
J. Yang, Y. Zhou, and Y. Guan, “PPARγ as a therapeutic target in diabetic nephropathy and other renal diseases,” Current Opinion in Nephrology and Hypertension, vol. 21, no. 1, pp. 97–105, 2012.
View at: Publisher Site | Google Scholar
T. Kanjanabuch, L.-J. Ma, J. Chen et al., “PPAR-γ agonist protects podocytes from injury,” Kidney International, vol. 71, no. 12, pp. 1232–1239, 2007.
View at: Publisher Site | Google Scholar
J. M. Rutkowski, Z. V. Wang, A. S. D. Park et al., “Adiponectin promotes functional recovery After podocyte ablation,” Journal of the American Society of Nephrology, vol. 24, no. 2, pp. 268–282, 2013.
View at: Publisher Site | Google Scholar
G. J. Ko, Y. S. Kang, S. Y. Han et al., “Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats,” Nephrology Dialysis Transplantation, vol. 23, no. 9, pp. 2750–2760, 2008.
View at: Publisher Site | Google Scholar
B. Guo, D. Koya, M. Isono, T. Sugimoto, A. Kashiwagi, and M. Haneda, “Peroxisome proliferator-activated receptor- $γ$ ligands inhibit TGF- $β$ 1-induced fibronectin expression in glomerular mesangial cells,” Diabetes, vol. 53, no. 1, pp. 200–208, 2004.
View at: Publisher Site | Google Scholar
T. Fujita, Y. Sugiyama, S. Taketomi et al., “Reduction of insulin resistance in obese and/or diabetic animals by 5-[4-(1-methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3878, U-63,287, Ciglitazone), a new antidiabetic agent,” Diabetes, vol. 32, no. 9, pp. 804–810, 1983.
View at: Publisher Site | Google Scholar
S. A. Kliewer, J. M. Lenhard, T. M. Willson, I. Patel, D. C. Morris, and J. M. Lehmann, “A prostaglandin J₂ metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation,” Cell, vol. 83, no. 5, pp. 813–819, 1995.
View at: Publisher Site | Google Scholar
J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer, “An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ),” Journal of Biological Chemistry, vol. 270, no. 22, pp. 12953–12956, 1995.
View at: Publisher Site | Google Scholar
Y. Miyazaki and R. A. DeFronzo, “Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion, glucose tolerance and adipocytokines in type 2 diabetic patients,” Diabetes, Obesity and Metabolism, vol. 10, no. 12, pp. 1204–1211, 2008.
View at: Publisher Site | Google Scholar
Y. Miyazaki, A. Mahankali, M. Matsuda et al., “Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone,” Diabetes Care, vol. 24, no. 4, pp. 710–719, 2001.
View at: Publisher Site | Google Scholar
A. Gastaldelli, Y. Miyazaki, M. Pettiti et al., “The effect of rosiglitazone on the liver: decreased gluconeogenesis in patients with type 2 diabetes,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 3, pp. 806–812, 2006.
View at: Publisher Site | Google Scholar
R. A. Defronzo, “From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus,” Diabetes, vol. 58, no. 4, pp. 773–795, 2009.
View at: Publisher Site | Google Scholar
A. Gastaldelli, Y. Miyazaki, A. Mahankali et al., “The effect of pioglitazone on the liver: role of adiponectin,” Diabetes Care, vol. 29, no. 10, pp. 2275–2281, 2006.
View at: Publisher Site | Google Scholar
J. H. Choi, A. S. Banks, J. L. Estall et al., “Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ 3 by Cdk5,” Nature, vol. 466, no. 7305, pp. 451–456, 2010.
View at: Publisher Site | Google Scholar
A. S. Banks, F. E. McAllister, J. P. Camporez et al., “An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ,” Nature, vol. 517, no. 7534, pp. 391–395, 2014.
View at: Publisher Site | Google Scholar
K. J. McCarthy, R. E. Routh, W. Shaw, K. Walsh, T. C. Welbourne, and J. H. Johnson, “Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion,” Kidney International, vol. 58, no. 6, pp. 2341–2350, 2000.
View at: Publisher Site | Google Scholar
T. Yoshimoto, M. Naruse, M. Nishikawa et al., “Antihypertensive and vasculo- and renoprotective effects of pioglitazone in genetically obese diabetic rats,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 272, no. 6, pp. E989–E996, 1997.
View at: Google Scholar
J. Weissgarten, S. Berman, S. Efrati, M. Rapoport, Z. Averbukh, and L. Feldman, “Apoptosis and proliferation of cultured mesangial cells isolated from kidneys of rosiglitazone-treated pregnant diabetic rats,” Nephrology Dialysis Transplantation, vol. 21, no. 5, pp. 1198–1204, 2006.
View at: Publisher Site | Google Scholar
C. Weigert, K. Brodbeck, A. Bierhaus, H. U. Häring, and E. D. Schleicher, “c-Fos-driven transcriptional activation of transforming growth factor beta-1: inhibition of high glucose-induced promoter activity by thiazolidinediones,” Biochemical and Biophysical Research Communications, vol. 304, no. 2, pp. 301–307, 2003.
View at: Publisher Site | Google Scholar
S. Yoshioka, H. Nishino, T. Shiraki et al., “Antihypertensive effects of CS-045 treatment in obese Zucker rats,” Metabolism: Clinical and Experimental, vol. 42, no. 1, pp. 75–80, 1993.
View at: Publisher Site | Google Scholar
P. A. Sarafidis and G. L. Bakris, “Protection of the kidney by thiazolidinediones: an assessment from bench to bedside,” Kidney International, vol. 70, no. 7, pp. 1223–1233, 2006.
View at: Publisher Site | Google Scholar
T. Nakamura, C. Ushiyama, N. Shimada, K. Hayashi, I. Ebihara, and H. Koide, “Comparative effects of pioglitazone, glibenclamide, and voglibose on urinary endothelin-1 and albumin excretion in diabetes patients,” Journal of Diabetes and its Complications, vol. 14, no. 5, pp. 250–254, 2000.
View at: Publisher Site | Google Scholar
T. Nakamura, C. Ushiyama, S. Osada, M. Hara, N. Shimada, and H. Koide, “Pioglitazone reduces urinary podocyte excretion in type 2 diabetes patients with microalbuminuria,” Metabolism: Clinical and Experimental, vol. 50, no. 10, pp. 1193–1196, 2001.
View at: Publisher Site | Google Scholar
R. A. DeFronzo, D. Tripathy, D. C. Schwenke et al., “Pioglitazone for diabetes prevention in impaired glucose tolerance,” The New England Journal of Medicine, vol. 364, no. 12, pp. 1104–1115, 2011.
View at: Publisher Site | Google Scholar
T. Yanagawa, A. Araki, K. Sasamoto, S. Shirabe, and T. Yamanouchi, “Effect of antidiabetic medications on microalbuminuria in patients with type 2 diabetes,” Metabolism, vol. 53, no. 3, pp. 353–357, 2004.
View at: Publisher Site | Google Scholar
K. Aljabri, S. E. Kozak, and D. M. Thompson, “Addition of pioglitazone or bedtime insulin to maximal doses of sulfonylurea and metformin in type 2 diabetes patients with poor glucose control: a prospective, randomized trial,” American Journal of Medicine, vol. 116, no. 4, pp. 230–235, 2004.
View at: Publisher Site | Google Scholar
B. Cariou, B. Charbonnel, and B. Staels, “Thiazolidinediones and PPARγ agonists: time for a reassessment,” Trends in Endocrinology and Metabolism, vol. 23, no. 5, pp. 205–215, 2012.
View at: Publisher Site | Google Scholar
J. V. Huang, C. R. Greyson, and G. G. Schwartz, “PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty,” Journal of Lipid Research, vol. 53, no. 9, pp. 1738–1754, 2012.
View at: Publisher Site | Google Scholar
A. Benbow, M. Stewart, and G. Yeoman, “Thiazolidinediones for type 2 diabetes. All glitazones may exacerbate heart failure,” British Medical Journal, vol. 322, article 236, 2001.
View at: Publisher Site | Google Scholar
E. Erdmann and R. G. Wilcox, “Weighing up the cardiovascular benefits of thiazolidinedione therapy: the impact of increased risk of heart failure,” European Heart Journal, vol. 29, no. 1, pp. 12–20, 2008.
View at: Publisher Site | Google Scholar
K. B. Sotiropoulos, A. Clermont, Y. Yasuda et al., “Adipose-specific effect of rosiglitazone on vascular permeability and protein kinase C activation: novel mechanism for PPAR $γ$ agonist's effects on edema and weight gain,” The FASEB Journal, vol. 20, no. 8, pp. 1203–1205, 2006.
View at: Publisher Site | Google Scholar
D. Kotake and N. Hirasawa, “Activation of a retinoic acid receptor pathway by thiazolidinediones induces production of vascular endothelial growth factor/vascular permeability factor in OP9 adipocytes,” European Journal of Pharmacology, vol. 707, no. 1–3, pp. 95–103, 2013.
View at: Publisher Site | Google Scholar
A. D. Dede, S. Tournis, I. Dontas, and G. Trovas, “Type 2 diabetes mellitus and fracture risk,” Metabolism, vol. 63, no. 12, pp. 1480–1490, 2014.
View at: Publisher Site | Google Scholar
A. Grey, M. Bolland, S. Fenwick et al., “The skeletal effects of pioglitazone in type 2 diabetes or impaired glucose tolerance: a randomized controlled trial,” European Journal of Endocrinology, vol. 170, no. 2, pp. 255–262, 2014.
View at: Publisher Site | Google Scholar
J. P. Bilezikian, R. G. Josse, R. Eastell et al., “Rosiglitazone decreases bone mineral density and increases bone turnover in postmenopausal women with type 2 diabetes mellitus,” Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 4, pp. 1519–1528, 2013.
View at: Publisher Site | Google Scholar
M. Monami, I. Dicembrini, and E. Mannucci, “Thiazolidinediones and cancer: results of a meta-analysis of randomized clinical trials,” Acta Diabetologica, vol. 51, no. 1, pp. 91–101, 2014.
View at: Publisher Site | Google Scholar
J. A. Dormandy, B. Charbonnel, D. J. A. Eckland et al., “Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events): a randomised controlled trial,” The Lancet, vol. 366, no. 9493, pp. 1279–1289, 2005.
View at: Publisher Site | Google Scholar
R. W. Nesto, D. Bell, R. O. Bonow et al., “Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association,” Diabetes Care, vol. 27, no. 1, pp. 256–263, 2004.
View at: Publisher Site | Google Scholar
P. Raskin, M. Rendell, M. C. Riddle, J. F. Dole, M. I. Freed, and J. Rosenstock, “A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes,” Diabetes Care, vol. 24, no. 7, pp. 1226–1232, 2001.
View at: Publisher Site | Google Scholar
P. A. Sarafidis, P. I. Georgianos, and A. N. Lasaridis, “PPAR- $γ$ agonism for cardiovascular and renal protection,” Cardiovascular Therapeutics, vol. 29, no. 6, pp. 377–384, 2011.
View at: Publisher Site | Google Scholar
E. Erdmann, J. A. Dormandy, B. Charbonnel, M. Massi-Benedetti, I. K. Moules, and A. M. Skene, “The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) study,” Journal of the American College of Cardiology, vol. 49, no. 17, pp. 1772–1780, 2007.
View at: Publisher Site | Google Scholar
R. M. Lago, P. P. Singh, and R. W. Nesto, “Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials,” The Lancet, vol. 370, no. 9593, pp. 1129–1136, 2007.
View at: Publisher Site | Google Scholar
R. W. Nesto, D. Bell, R. O. Bonow et al., “Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association,” Circulation, vol. 108, no. 23, pp. 2941–2948, 2003.
View at: Publisher Site | Google Scholar
G. Hong, A. Lockhart, B. Davis et al., “PPAR gamma activation enhances cell surface ENaCalpha via up-regulation of SGK1 in human collecting duct cells,” The FASEB Journal, vol. 17, no. 13, pp. 1966–1968, 2003.
View at: Google Scholar
S. Muto, Y. Miyata, M. Imai, and Y. Asano, “Troglitazone stimulates basolateral rheogenic Na⁺/HCO^-₃ cotransport activity in rabbit proximal straight tubules,” Nephron Experimental Nephrology, vol. 9, no. 3, pp. 191–197, 2001.
View at: Publisher Site | Google Scholar
A. Zanchi, A. Chiolero, M. Maillard, J. Nussberger, H.-R. Brunner, and M. Burnier, “Effects of the peroxisomal proliferator-activated receptor-γ agonist pioglitazone on renal and hormonal responses to salt in healthy men,” The Journal of Clinical Endocrinology & Metabolism, vol. 89, no. 3, pp. 1140–1145, 2004.
View at: Publisher Site | Google Scholar
J. M. Gonzalez-Campoy, J. C. Romero, and F. G. Knox, “Escape from the sodium-retaining effects of mineralocorticoids: role of ANF and intrarenal hormone systems,” Kidney International, vol. 35, no. 3, pp. 767–777, 1989.
View at: Publisher Site | Google Scholar
S. C. Kiley and R. L. Chevalier, “Species differences in renal Src activity direct EGF receptor regulation in life or death response to EGF,” The American Journal of Physiology—Renal Physiology, vol. 293, no. 3, pp. F895–F903, 2007.
View at: Publisher Site | Google Scholar
E. Burgermeister and R. Seger, “PPAR $γ$ and MEK interactions in cancer,” PPAR Research, vol. 2008, Article ID 309469, 16 pages, 2008.
View at: Publisher Site | Google Scholar
S. Kousteni, T. Bellido, L. I. Plotkin et al., “Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity,” Cell, vol. 104, no. 5, pp. 719–730, 2001.
View at: Google Scholar
Y. Li, H. Yamada, Y. Kita et al., “Roles of ERK and cPLA2 in the angiotensin II-mediated biphasic regulation of Na⁺-HCO₃⁻ transport,” Journal of the American Society of Nephrology, vol. 19, no. 2, pp. 252–259, 2008.
View at: Publisher Site | Google Scholar
D.-H. Lee, D.-B. Park, Y.-K. Lee et al., “The effects of thiazolidinedione treatment on the regulations of aquaglyceroporins and glycerol kinase in OLETF rats,” Metabolism: Clinical and Experimental, vol. 54, no. 10, pp. 1282–1289, 2005.
View at: Publisher Site | Google Scholar
L. Zhou, G. Liu, Z. Jia et al., “Increased susceptibility of db/db mice to rosiglitazone-induced plasma volume expansion: role of dysregulation of renal water transporters,” American Journal of Physiology—Renal Physiology, vol. 305, no. 10, pp. F1491–F1497, 2013.
View at: Publisher Site | Google Scholar
B. Edemir, H. Pavenstädt, E. Schlatter, and T. Weide, “Mechanisms of cell polarity and aquaporin sorting in the nephron,” Pflügers Archiv European Journal of Physiology, vol. 461, no. 6, pp. 607–621, 2011.
View at: Publisher Site | Google Scholar
M. L. A. Kortenoeven and R. A. Fenton, “Renal aquaporins and water balance disorders,” Biochimica et Biophysica Acta—General Subjects, vol. 1840, no. 5, pp. 1533–1549, 2014.
View at: Publisher Site | Google Scholar
J. L. Wilson, C. A. Miranda, and M. A. Knepper, “Vasopressin and the regulation of aquaporin-2,” Clinical and Experimental Nephrology, vol. 17, no. 6, pp. 751–764, 2013.
View at: Publisher Site | Google Scholar
T. Ma, Y. Song, B. Yang et al., “Nephrogenic diabetes insipidus in mice lacking aquaporin-3 water channels,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 8, pp. 4386–4391, 2000.
View at: Publisher Site | Google Scholar
H. Castrop and I. M. Schiessl, “Physiology and pathophysiology of the renal Na-K-2Cl cotransporter (NKCC2),” The American Journal of Physiology: Renal Physiology, vol. 307, no. 9, pp. F991–F1002, 2014.
View at: Publisher Site | Google Scholar
N. Markadieu and E. Delpire, “Physiology and pathophysiology of SLC12A1/2 transporters,” Pflugers Archiv European Journal of Physiology, vol. 466, no. 1, pp. 91–105, 2014.
View at: Publisher Site | Google Scholar
Y. Fu, M. Gerasimova, F. Batz et al., “PPARγ agonist-induced fluid retention depends on aENaC expression in connecting tubules,” Nephron, vol. 129, no. 1, pp. 68–74, 2015.
View at: Publisher Site | Google Scholar
H. S. Chou, K. E. Truitt, J. B. Moberly et al., “A 26-week, placebo- and pioglitazone-controlled monotherapy study of rivoglitazone in subjects with type 2 diabetes mellitus,” Diabetes, Obesity and Metabolism, vol. 14, no. 11, pp. 1000–1009, 2012.
View at: Publisher Site | Google Scholar
A. M. DePaoli, L. S. Higgins, R. R. Henry, C. Mantzoros, F. L. Dunn, and INT131-007 Study Group, “Can a selective PPARγ modulator improve glycemic control in patients with type 2 diabetes with fewer side effects compared with pioglitazone?” Diabetes Care, vol. 37, no. 7, pp. 1918–1923, 2014.
View at: Publisher Site | Google Scholar

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Copyright © 2015 Shoko Horita et al. 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.

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