Obesity Hypertension: The Regulatory Role of Leptin

Kshatriya, Shilpa; Liu, Kan; Salah, Ali; Szombathy, Tamas; Freeman, Ronald H.; Reams, Garry P.; Spear, Robert M.; Villarreal, Daniel

doi:https://doi.org/10.4061/2011/270624

International Journal of Hypertension

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Difficult to Treat or Resistant Hypertension: Etiology, Pathophysiology, and Innovative Therapies

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Volume 2011 | Article ID 270624 | https://doi.org/10.4061/2011/270624

Obesity Hypertension: The Regulatory Role of Leptin

Shilpa Kshatriya,¹Kan Liu,¹Ali Salah,¹Tamas Szombathy,¹Ronald H. Freeman,²Garry P. Reams,²Robert M. Spear,¹and Daniel Villarreal^1,3

Academic Editor: Vasilios Papademetriou

Received27 Sept 2010

Accepted15 Dec 2010

Published03 Jan 2011

Abstract

Leptin is a 16-kDa-peptide hormone that is primarily synthesized and secreted by adipose tissue. One of the major actions of this hormone is the control of energy balance by binding to receptors in the hypothalamus, leading to reduction in food intake and elevation in temperature and energy expenditure. In addition, increasing evidence suggests that leptin, through both direct and indirect mechanisms, may play an important role in cardiovascular and renal regulation. While the relevance of endogenous leptin needs further clarification, it appears to function as a pressure and volume-regulating factor under conditions of health. However, in abnormal situations characterized by chronic hyperleptinemia such as obesity, it may function pathophysiologically for the development of hypertension and possibly also for direct renal, vascular, and cardiac damage.

1. Introduction

The prevalence of obesity in the adult population of the United States has risen markedly in the last three decades, contributing to the increased incidence of diabetes, hypertension, and heart disease [1–3]. Indeed, epidemiological studies suggest that 65–75% of the risk for hypertension is attributed to excess weight [4, 5]. Recently, a novel and most promising area of research in obesity and hypertension that links these two pathologic conditions is the endocrinology of adipose tissue. It is now apparent that adipose tissue is a prolific organ which secretes several immunomodulators and bioactive molecules [3, 6]. Of these various factors, leptin has emerged as an important hormone with significant pleiotropic actions on several organ systems [7, 8].

The first described major action of leptin was on the hypothalamus to control body weight and fat deposition through its effects on appetite inhibition, as well as stimulation of the metabolic rate and thermogenesis [9, 10]. However, increasing evidence suggests that the biology of leptin extends to other organs including the kidney, the heart, the sympathetic nervous system, and the systemic vasculature, areas in which it may have prominent effects [7, 8, 11–14].

2. Leptin Receptors: Localization and Function

The leptin receptor (LR), a product of the lepr gene, is a member of the extended class I cytokine receptor family having at least six splice variants LR (a-f) [15–19]. Significant expression of the lepr gene occurs in the lung and adipocytes, while only moderate levels appear in the kidney, with relatively lower levels demonstrated in other tissues like the heart, brain, spleen, liver, and muscle [20]. Though the extracellular domain of the leptin receptor and the short splice variant (LRa) have been detected in many peripheral tissues, the long splice variant (LRb) is expressed in fewer organ systems including the adrenal gland, kidney, and heart [20]. This long splice variant leads to activation of the Janus Kinases (a family of tyrosine kinases) to promote transcription through activation of the STAT-3 (signal transduction and activator of transcription) and PI3K (phosphoinositol-3 kinase), and inhibition of AMPK (AMP-activated protein kinase) [15–20]. LRa and LRb can also stimulate MAPK (mitogen activated protein kinase) which may be involved in the induction of hypertrophy [21]. Finally, SOCS-3 (suppression of cytokine signaling protein) and PTB1b (protein tyrosine phosphatase 1b) have been identified as negative regulators of leptin signaling [15–19].

3. Leptin, Sympathetic Nervous System, and the Regulation of Arterial Blood Pressure

It is now well established that leptin can activate the sympathetic nervous system both by local peripheral actions as well as through centrally mediated effects on the hypothalamus [22]. Studies with direct infusion of leptin into the cerebral ventricles of normal rats have demonstrated a slow increase of mean arterial pressure (MAP) of approximately 10% [13]. Moreover, recent investigations have suggested that leptin signaling in the nucleus tracti solitarii increased renal sympathetic flow in normal rats but not in obese Zucker rats, indicating that intact leptin receptors are essential for this vasoactive response [22]. In agreement with these concepts, human studies have suggested that genetically mediated leptin deficiency is associated not only with morbid obesity, but also impairment in the sympathetic nervous system activity and postural hypotension in homozygous children and adults [23].

However, it is important to point out that in other investigations conducted both in normotensive as well as hypertensive rats [12, 14, 24], the acute systemic administration of leptin was associated with the peripheral activation of the sympathetic nervous system without elevation in MAP. This raises the possibility of the simultaneous local activation of counter-regulatory vasodilatory mechanisms [14, 25, 26]. In vitro studies have demonstrated a dose-dependent leptin-induced vasorelaxation in the aortic rings of Wistar-Kyoto rats [25] which is mediated by nitric oxide (NO) and possibly by endothelial-derived hyperpolarizing factor (EDHF). An elevation in plasma NO with intravenous administration of synthetic leptin in normal rats has also been demonstrated [26]. In these studies blockade of NO led to a leptin-induced enhancement of arterial blood pressure while blockade of the sympathetic nervous system led to leptin-mediated reduction in blood pressure [26]. Thus, leptin’s lack of effect on arterial blood pressure in normal subjects may represent a balanced action of vasodilatation primarily mediated by NO and vasoconstriction primarily mediated by the sympathetic nervous system, with a resultant neutral hemodynamic effect [26, 27]. This concept requires further validation because the vasodilatory actions of leptin in other vascular beds have been found to be inconsistent [28, 29]. In high-calorie fed obese rats, however, recent studies by Beltowski et al have indicated that acutely infused leptin was associated with a hypertensive effect related, at least in part, to impaired vascular NO and EDHF production characteristic of obesity [30].

4. Chronic Hyperleptinemia, Leptin Resistance, and Hypertension

In chronic hyperleptinemic conditions such as obesity, the potential neutral effect of leptin on peripheral vascular resistance may no longer be present. It has been previously demonstrated that the agouti yellow obese mouse model is resistant to the satiety actions of leptin but not to the effects of leptin on the sympathetic nervous system [31, 32], although this stimulation may be attenuated with the progression of obesity [33]. From these findings, the concept of “selective leptin resistance” as a mechanism for the development of hypertension in obesity has emerged [31, 32]. The precise factors behind this selectivity are yet to be fully defined [32, 34], but may involve alterations in the SOCS3 signaling pathway or IRS-1 (insulin receptor substrate-1) serine residue phosphorylation [30, 35, 36].

Independent of the possibility of selective leptin resistance in obesity, studies in normal rats have demonstrated that chronic hyperleptinemia leads to a persistent elevation in MAP and this hypertensive effect is rapidly reversed upon cessation of the hormone administration [37]. Similar increases in systolic blood pressure have been demonstrated in transgenic mice overexpressing leptin where the endogenous level of the hormone was elevated twenty-fold [38]. In this regard, it is pertinent to point out that hyperleptinemia may increase vascular smooth muscle cell proliferation [38], an effect that could contribute to the development and/or perpetuation of hypertension. Moreover, mice with leptin deficiency (ob/ob) or with a leptin receptor defect (db/db) exhibit significant obesity but do not develop hypertension, suggesting that at least in animal models, leptin may play a role in the regulation of systemic hemodynamics [32]. In humans, emerging evidence suggests a direct relationship between hyperleptinemia and hypertension in both men and women [39, 40], and this effect may be independent of BMI and insulin resistance. In a recent study by Shankar and Xiao of 5,599 Americans, higher plasma leptin levels were positively associated with hypertension after adjusting for multiple covariates including age, sex, race/ethnicity, education, smoking, body mass index, diabetes mellitus, and serum cholesterol [41]. In this regard, recent studies indicating a reduction in serum leptin levels with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers suggest a potential interaction between leptin and the renin-angiotensin-aldosterone system for hemodynamic regulation in obesity [42, 43].

Finally, an additional potential mechanism involved in leptin’s regulation of blood pressure implicates the melanocortin system [44]. Recent investigations have suggested that the acute actions of leptin to raise renal sympathetic activity are abolished in Melanocortin 4 receptor-(MC4R-) deficient (−/−) mice, suggesting that the MC4R may mediate the sympathoexcitatory actions of leptin [45]. To this end, Greenfield et al. demonstrated a lower prevalence of hypertension in obese subjects with a loss-of-function mutation in MC4R gene compared to obese controls with the intact gene again implicating melanocortinergic signaling in the control of systemic hemodynamics [46].

5. Leptin and the Regulation of Sodium-Volume Balance

Previous studies have indicated that the LRb leptin receptor is localized in the renal medulla [20, 47] which suggests a functional role of this hormone in renal biology. In the last 5–10 years, numerous studies have demonstrated that acute administration of synthetic leptin in the rat produces a significant elevation in urinary sodium and water excretion [14, 47–49].

Villarreal et al. [14] demonstrated that in normotensive rats, an intravenous bolus of leptin produced a robust six to sevenfold elevation in urinary sodium excretion and fractional excretion of sodium; in contrast, hypertensive rats were refractory to the renal effects of leptin. Interestingly, the natriuretic effect was attenuated in obese Zucker rats [14]. MAP and creatinine clearance remained unchanged in all of the rat strains with the acute infusion of the hormone. Collectively, these findings were interpreted to suggest that leptin might be a natriuretic hormone primarily acting at the tubular level for promotion of sodium and water excretion in normal rats, and that leptin may function pathophysiologically in obesity and hypertension, where chronic hyperleptinemia may contribute to a preferential stimulation of the sympathetic nervous system with further elevation in blood pressure and reduced sodium and water excretion [2, 7, 50]. Moreover, in a rat model of diet-induced obesity, initial studies by Patel et al. have shown markedly attenuated natriuretic and diuretic effects of synthetic leptin as well as reduced urinary excretion of NO [51]. These findings suggest that in obesity, alterations in leptin-induced renal NO production and/or metabolism may account, at least in part, for the blunted natriuretic effects. However, additional observations in diet-induced obese rats indicate that caloric restriction was associated with the restoration of the natriuretic actions of leptin as well as with the renal generation of NO [51]. In the aggregate, these studies are consistent with the concept that obesity is associated with renal leptin resistance [14, 52], and this resistance, at least in part, is reversible with caloric restriction and weight loss.

The significance of NO in the direct modulation of leptin-induced sodium excretion has been investigated in rats chronically treated with L-NAME to inhibit NO production [53]. L-NAME-treated rats failed to produce significant natriuresis. However, there was a two to threefold elevation in sodium excretion induced by leptin with the restoration of NO by sodium nitroprusside [53], indicating that NO may play an important role in mediating or modulating the tubular natriuretic effects of leptin. These observations are supported by the studies of Beltowski et al., [52] which demonstrated that leptin produces a time- and dose-dependent reduction of renal medullary Na-K-ATPase, which may in part be regulated by NO [53, 54]. Beltowski et al., [52] also reported that in diet-induced obese rats, leptin-induced stimulation of plasma NO, reduction of renal Na-K-ATPase, and natriuresis are all significantly impaired.

The mechanisms for renal resistance to leptin in obesity and hypertension are not completely defined but may include receptor down regulation [12, 51], postreceptor signaling alterations [12, 16, 17], excessive degradation of NO produced by oxidative stress [55], or increased activation of the efferent renal sympathetic nervous system leading to antinatriuresis [49]. Indeed, studies which [49] have examined this latter hypothesis using an animal model of renal denervation indicate that the renal efferent sympathetic nervous system is an important counter-regulatory mechanism impeding leptin-induced sodium excretion in hypertension, and perhaps also during obesity, which is similarly characterized by a heightened sympathetic nervous tone [2, 7].

The relevance of endogenous leptin as a distinct sodium-volume regulatory hormone has been examined in normal Sprague Dawley rats that were in a state of mild sodium/volume expansion [56]. Urinary sodium and volume excretion were significantly reduced by approximately 20–25% after blockade of leptin with a polyclonal antibody, indicating an important physiologic role for this hormone in the daily renal control of salt and water balance. The importance of leptin as a regulator of sodium and volume is further supported by recent investigations [56, 57] which have demonstrated that leptin expression in adipose tissue is directly proportional to dietary sodium, a response that would be expected for mechanisms regulating sodium balance.

Thus, the available information to date suggests that leptin's net effect on renal sodium metabolism and ultimately systemic hemodynamics may reflect both direct natriuretic and indirect antinatriuretic actions. The responsiveness to leptin at neural, renal, and other sites which regulate natriuresis and vascular resistance may differ under diverse physiological and pathophysiological conditions, and this in turn, will be a determinant for the overall magnitude of leptin-induced sodium, water, and hemodynamic balance.

6. Leptin and Chronic Renal Insufficiency

Leptin’s role in renal physiology and pathophysiology is complex. As previously discussed, leptin may play a significant role in the regulation of sodium and water balance in normal situations. However, in conditions of chronic hyperleptinemia, the hormone has been linked to renal structural changes that specifically have been associated with obesity [58]. Elegant studies by Wolf et al. [59] have determined that in glomerular endothelial cells, leptin can stimulate cellular proliferation, expression of TGF-β1 and type IV collagen synthesis leading to fibrosis. Indeed, chronic infusion of leptin in normal rats promoted the development of glomerulosclerosis and proteinuria [59]. It is of interest that similar renal abnormalities have been found in mice with chronic high fat diet and the metabolic syndrome [60], which is characterized by sustained elevations of circulating leptin [61].

Inappropriate elevation in serum leptin levels has been demonstrated in patients with chronic kidney disease [62–64]. The origin and significance of hyperleptinemia in these patients are not completely defined, but it is important to emphasize that the marked elevation of leptin is out of proportion to obesity and persists after correction for body mass index [65]. Since the kidney is involved in clearance of leptin, its elevated levels in renal insufficiency are primarily due to reduced renal filtration and metabolism [62, 66]. It remains to be determined whether an increased rate of leptin production also contributes to the high serum leptin levels in renal insufficiency.

Leptin levels appear to be higher in patients receiving peritoneal dialysis (PD) compared to hemodialysis (HD) [67]. The reasons for this phenomenon are multifactorial. It is likely that the elevated body fat mass in patients with PD contributes to the increase in serum leptin [67]. However, other factors are probably involved. For instance, the continuous glucose load in PD results in chronic hyperinsulinemia, an important finding considering that insulin upregulates lepr gene expression [63]. In this regard, it is of interest that even higher leptin levels are observed in patients with renal insufficiency with elevated insulin levels compared to patients with low insulin levels [63, 68].

The pathophysiological significance of hyperleptinemia in renal insufficiency is not completely understood. High levels of leptin have been associated with weight loss in dialysis patients [65, 69–71], and therefore it has been suggested that hyperleptinemia may be a contributing factor in uremic-induced cachexia [64, 69–74]. Other suggested actions in patients with end-stage renal disease which include leptin-induced reduction in erythropoiesis [75, 76], promotion of renal osteodystrophy [77, 78], and chronic inflammation [63, 78, 79].

7. Leptin and the Heart

It is now well recognized that the role of leptin in energy homeostasis extends into cardiac metabolism. The effects of leptin mediated by the LRb receptor include a reduction of insulin signaling with enhanced lipid oxidation and therefore inhibition of anabolic pathways [80]. Similar to the kidney, chronic hyperleptinemia may be indirectly important in the development of cardiac disease via sympathetic activation, pressor effects, enhancement of platelet aggregation, impairment of fibrinolysis as well as proangiogenic actions [12, 35, 81, 82] and systemic inflammation via leptin-induced expression of C-reactive protein [83, 84].

In addition, and although still controversial, leptin may be involved in the pathogenesis of myocyte hypertrophy and cardiac dysfunction [85–87] through direct effects. Indeed, leptin can proliferate, differentiate, and functionally activate hemopoietic and embryonic cells to promote myocyte growth [88–90]. Moreover, in rats with myocardial infarction, cardiac hypertrophy has been shown to be attenuated with the blockade of leptin receptors [91]. Among the suggested mechanisms of leptin-induced hypertrophy are the stimulation of endothelin-1, angiotensin II [92], and reactive oxygen species [93]. Additional studies in rats with myocardial infarction have also indicated that long-term continuous administration of leptin promoted the development of eccentric cardiac hypertrophy [94].

In contrast to these investigations, studies in leptin-deficient mice (ob/ob) with [94, 95] or without myocardial infarction [96] have suggested that leptin can exert protective cardiac effects with reversal of baseline myocyte hypertrophy during leptin supplementation [96]. Also, Tajmir et al. [97] have indicated that leptin can activate ERK 1/2 (extracellular signal-regulated kinase) and phosphoinositol-3 kinase-dependent signaling pathways in cardiomyocytes to promote physiological repair of myocardium. Presently, the reasons for the apparent discrepant effects of leptin on myocyte growth are unclear, but may be related to different experimental conditions, including the variable response of leptin in neonatal compared to adult cells [82–97].

In addition to its potential actions on myocardial cell growth, leptin has been shown to exert direct negative inotropic effects on adult rat ventricular myocytes [98]. The suggested mechanisms involve activation of fatty acid oxidation leading to decreased triglyceride content or an altered adenylate cyclase function [96, 99]. Alternatively, Nickola et al. [98] reported that leptin may abnormally increase expression of Nitric Oxide Synthases in cardiac myocytes promoting oxidative stress and depressed cardiac function. However, similar to the controversy related to cardiac hypertrophy, more recent studies in ob/ob mice [95] or rats [94] with myocardial infarction have suggested that leptin may attenuate adverse cardiac remodeling by reducing apoptosis [95], which may improve left ventricular contractile function, and at least in part, increase survival [94–96].

The relevance of these studies in humans is unclear. Although there is evidence to suggest a direct relationship between the hyperleptinemia of obesity with cardiac hypertrophy [96, 100], and possibly heart failure [101], these are not consistent findings [8, 11]. Additional in vitro and in vivo studies are needed to define and characterize the potential beneficial or deleterious effects of leptin in cardiac physiology and pathophysiology.

8. Summary and Conclusions

It is well established that cardiovascular and renal functions require the activation of multiple neuro hormonal mechanisms designed to maintain homeostasis. The hormone leptin has multiple actions that may be important not only for energy metabolism, but also in physiological and pathophysiological cardiovascular and renal regulation (Figure 1). Potentially prominent are its effects on renal sodium excretion, NO, sympathetic nervous system activation, and vascular tone. The interaction among the vasoconstricting, vasodilatory, and natriuretic effects of leptin to help achieve volume and pressure homeostasis in normal conditions may be disrupted during chronic hyperleptinemia, and this effect could likely contribute to hypertension and possible cardiac and renal dysfunction. Further research awaits the additional characterization of both direct and indirect mechanisms of action of leptin, including its interface with other important hormonal sodium-volume-pressure regulatory systems, in both health and disease states, particularly obesity and related comorbidities.

Acknowledgments

This paper is supported in part by the Veteran Affairs Research Program (Merit Review), the Joseph C. Georg Research Award, and the Hendricks Research Award. The authors wish to acknowledge the expert technical assistance Jeffrey Montalbano.

References

C. L. Ogden, M. D. Carroll, L. R. Curtin, M. A. McDowell, C. J. Tabak, and K. M. Flegal, “Prevalence of overweight and obesity in the United States, 1999–2004,” Journal of the American Medical Association, vol. 295, no. 13, pp. 1549–1555, 2006.
View at: Publisher Site | Google Scholar
J. E. Hall, E. D. Crook, D. W. Jones, M. R. Wofford, and P. M. Dubbert, “Mechanisms of obesity-associated cardiovascular and renal disease,” American Journal of the Medical Sciences, vol. 324, no. 3, pp. 127–137, 2002.
View at: Google Scholar
G. R. Hajer, T. W. Van Haeften, and F. L. J. Visseren, “Adipose tissue dysfunction in obesity, diabetes, and vascular diseases,” European Heart Journal, vol. 29, no. 24, pp. 2959–2971, 2008.
View at: Publisher Site | Google Scholar
R. J. Garrison, W. B. Kannel, J. Stokes, and W. P. Castelli, “Incidence and precursors of hypertension in young adults: the Framingham offspring study,” Preventive Medicine, vol. 16, no. 2, pp. 235–251, 1987.
View at: Google Scholar
M. R. Wofford and J. E. Hall, “Pathophysiology and treatment of obesity hypertension,” Current Pharmaceutical Design, vol. 10, no. 29, pp. 3621–3637, 2004.
View at: Publisher Site | Google Scholar
L. Hutley and J. B. Prins, “Fat as an endocrine organ: relationship to the metabolic syndrome,” American Journal of the Medical Sciences, vol. 330, no. 6, pp. 280–289, 2005.
View at: Google Scholar
P. K. Guha, D. Villarreal, G. P. Reams, and R. H. Freeman, “Role of leptin in the regulation of body fluid volume and pressures,” American Journal of Therapeutics, vol. 10, no. 3, pp. 211–218, 2003.
View at: Google Scholar
V. Sharma and J. H. McNeill, “The emerging roles of leptin and ghrelin in cardiovascular physiology and pathophysiology,” Current Vascular Pharmacology, vol. 3, no. 2, pp. 169–180, 2005.
View at: Publisher Site | Google Scholar
A. Misra and A. Garg, “Leptin, its receptor and obesity,” Journal of Investigative Medicine, vol. 44, no. 9, pp. 540–548, 1996.
View at: Google Scholar
F. Lönnqvist, “The obese (ob) gene and its product leptin—a new route toward obesity treatment in man?” Monthly Journal of the Association of Physicians, vol. 89, no. 5, pp. 327–332, 1996.
View at: Google Scholar
J. Bełtowski, “Role of leptin in blood pressure regulation and arterial hypertension,” Journal of Hypertension, vol. 24, no. 5, pp. 789–801, 2006.
View at: Publisher Site | Google Scholar
W. G. Haynes, D. A. Morgan, S. A. Walsh, A. L. Mark, and W. I. Sivitz, “Receptor-mediated regional sympathetic nerve activation by leptin,” Journal of Clinical Investigation, vol. 100, no. 2, pp. 270–278, 1997.
View at: Google Scholar
J. C. Dunbar, Y. Hu, and H. Lu, “Intracerebroventricular leptin increases lumbar and renal sympathetic nerve activity and blood pressure in normal rats,” Diabetes, vol. 46, no. 12, pp. 2040–2043, 1997.
View at: Google Scholar
D. Villarreal, G. Reams, R. H. Freeman, and A. Taraben, “Renal effects of leptin in normotensive, hypertensive, and obese rats,” American Journal of Physiology, vol. 275, no. 6, pp. R2056–R2060, 1998.
View at: Google Scholar
H. Chen, O. Charlat, L. A. Tartaglia et al., “Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice,” Cell, vol. 84, no. 3, pp. 491–495, 1996.
View at: Publisher Site | Google Scholar
A. S. Banks, S. M. Davis, S. H. Bates, and M. G. Myers, “Activation of downstream signals by the long form of the leptin receptor,” Journal of Biological Chemistry, vol. 275, no. 19, pp. 14563–14572, 2000.
View at: Publisher Site | Google Scholar
H. Münzberg and M. G. Myers, “Molecular and anatomical determinants of central leptin resistance,” Nature Neuroscience, vol. 8, no. 5, pp. 566–570, 2005.
View at: Publisher Site | Google Scholar
L. A. Tartaglia, M. Dembski, X. Weng et al., “Identification and expression cloning of a leptin receptor, OB-R,” Cell, vol. 83, no. 7, pp. 1263–1271, 1995.
View at: Publisher Site | Google Scholar
M. Y. Wang, Y. T. Zhou, C. B. Newgard, and R. H. Unger, “A novel leptin receptor isoform in rat,” FEBS Letters, vol. 392, no. 2, pp. 87–90, 1996.
View at: Publisher Site | Google Scholar
N. Hoggard, J. G. Mercer, D. V. Rayner, K. Moar, P. Trayhurn, and L. M. Williams, “Localization of leptin receptor mRNA splice variants in murine peripheral tissues by RT-PCR and in situ hybridization,” Biochemical and Biophysical Research Communications, vol. 232, no. 2, pp. 383–387, 1997.
View at: Publisher Site | Google Scholar
V. Anubhuti and S. Arora, “Leptin and its metabolic interactions—an update,” Diabetes, Obesity and Metabolism, vol. 10, no. 11, pp. 973–993, 2008.
View at: Publisher Site | Google Scholar
A. L. Mark, K. Agassandian, D. A. Morgan, X. Liu, M. D. Cassell, and K. Rahmouni, “Leptin signaling in the nucleus tractus solitarii increases sympathetic nerve activity to the kidney,” Hypertension, vol. 53, no. 2, pp. 375–380, 2009.
View at: Publisher Site | Google Scholar
M. Ozata, I. C. Ozdemir, and J. Licinio, “Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 10, pp. 3686–3695, 1999.
View at: Google Scholar
J. Bełtowski, J. Jochem, G. Wójcicka, and K. Zwirska-Korczala, “Influence of intravenously administered leptin on nitric oxide production, renal hemodynamics and renal function in the rat,” Regulatory Peptides, vol. 120, no. 1–3, pp. 59–67, 2004.
View at: Publisher Site | Google Scholar
G. Lembo, C. Vecchione, L. Fratta et al., “Leptin induces direct vasodilation through distinct endothelial mechanisms,” Diabetes, vol. 49, no. 2, pp. 293–297, 2000.
View at: Google Scholar
G. Frühbeck, “Pivotal role of nitric oxide in the control of blood pressure after leptin administration,” Diabetes, vol. 48, no. 4, pp. 903–908, 1999.
View at: Google Scholar
R. D. Brook, R. L. Bard, P. F. Bodary et al., “Blood pressure and vascular effects of leptin in humans,” Metabolic Syndrome and Related Disorders, vol. 5, no. 3, pp. 270–274, 2007.
View at: Publisher Site | Google Scholar
J. L. Mitchell, D. A. Morgan, M. L. G. Correia, A. L. Mark, W. I. Sivitz, and W. G. Haynes, “Does leptin stimulate nitric oxide to oppose the effects of sympathetic activation?” Hypertension, vol. 38, no. 5, pp. 1081–1086, 2001.
View at: Google Scholar
S. M. Gardiner, P. A. Kemp, J. E. March, and T. Bennett, “Regional haemodynamic effects of recombinant murine or human leptin in conscious rats,” British Journal of Pharmacology, vol. 130, no. 4, pp. 805–810, 2000.
View at: Google Scholar
J. Bełtowski, G. Wójcicka, A. Jamroz-Wiśniewska, and A. Marciniak, “Resistance to acute NO-mimetic and EDHF-mimetic effects of leptin in the metabolic syndrome,” Life Sciences, vol. 85, no. 15-16, pp. 557–567, 2009.
View at: Publisher Site | Google Scholar
A. L. Mark, R. A. Shaffer, M. L. G. Correia, D. A. Morgan, C. D. Sigmund, and W. G. Haynes, “Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice,” Journal of Hypertension, vol. 17, no. 12, pp. 1949–1953, 1999.
View at: Google Scholar
M. L. G. Correia, W. G. Haynes, K. Rahmouni, D. A. Morgan, W. I. Sivitz, and A. L. Mark, “The concept of selective leptin resistance: evidence from agouti yellow obese mice,” Diabetes, vol. 51, no. 2, pp. 439–442, 2002.
View at: Google Scholar
D. A. Morgan, D. R. Thedens, R. Weiss, and K. Rahmouni, “Mechanisms mediating renal sympathetic activation to leptin in obesity,” American Journal of Physiology, vol. 295, no. 6, pp. R1730–R1736, 2008.
View at: Publisher Site | Google Scholar
K. Rahmouni, M. L. G. Correia, W. G. Haynes, and A. L. Mark, “Obesity-associated hypertension: New insights into mechanisms,” Hypertension, vol. 45, no. 1, pp. 9–14, 2005.
View at: Publisher Site | Google Scholar
J. D. Tune and R. V. Considine, “Effects of leptin on cardiovascular physiology,” Journal of the American Society of Hypertension, vol. 1, no. 4, pp. 231–241, 2007.
View at: Publisher Site | Google Scholar
C. Bjorbaek, J. K. Elmquist, J. D. Frantz, S. E. Shoelson, and J. S. Flier, “Identification of SOCS-3 as a potential mediator of central leptin resistance,” Molecular Cell, vol. 1, no. 4, pp. 619–625, 1998.
View at: Google Scholar
E. W. Shek, M. W. Brands, and J. E. Hall, “Chronic leptin infusion increases arterial pressure,” Hypertension, vol. 31, no. 1, pp. 409–414, 1998.
View at: Google Scholar
F. Huang, X. Xiong, H. Wang, S. You, and H. Zeng, “Leptin-induced vascular smooth muscle cell proliferation via regulating cell cycle, activating ERK1/2 and NF-κB,” Acta Biochimica et Biophysica Sinica, vol. 42, no. 5, pp. 325–331, 2010.
View at: Publisher Site | Google Scholar
F. Galletti, L. D'Elia, G. Barba et al., “High-circulating leptin levels are associated with greater risk of hypertension in men independently of body mass and insulin resistance: results of an eight-year follow-up study,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 10, pp. 3922–3926, 2008.
View at: Publisher Site | Google Scholar
D. Ma, M. F. Feitosa, J. B. Wilk et al., “Leptin is associated with blood pressure and hypertension in women from the National Heart, Lung, and Blood Institute family heart study,” Hypertension, vol. 53, no. 3, pp. 473–479, 2009.
View at: Publisher Site | Google Scholar
A. Shankar and J. Xiao, “Positive relationship between plasma leptin level and hypertension,” Hypertension, vol. 56, no. 4, pp. 623–628, 2010.
View at: Publisher Site | Google Scholar
R. Fogari, G. Derosa, A. Zoppi et al., “Comparison of the effects of valsartan and felodipine on plasma leptin and insulin sensitivity in hypertensive obese patients,” Hypertension Research, vol. 28, no. 3, pp. 209–214, 2005.
View at: Publisher Site | Google Scholar
E. L. Santos, K. de Picoli Souza, E. D. da Silva et al., “Long term treatment with ACE inhibitor enalapril decreases body weight gain and increases life span in rats,” Biochemical Pharmacology, vol. 78, no. 8, pp. 951–958, 2009.
View at: Publisher Site | Google Scholar
W. G. Haynes, D. A. Morgan, A. Djalali, W. I. Sivitz, and A. L. Mark, “Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic,” Hypertension, vol. 33, no. 1, part 2, pp. 542–547, 1999.
View at: Google Scholar
K. Rahmouni, W. G. Haynes, D. A. Morgan, and A. L. Mark, “Role of melanocortin-4 receptors in mediating renal sympathoactivation to leptin and insulin,” Journal of Neuroscience, vol. 23, no. 14, pp. 5998–6004, 2003.
View at: Google Scholar
J. R. Greenfield, J. W. Miller, J. M. Keogh et al., “Modulation of blood pressure by central melanocortinergic pathways,” New England Journal of Medicine, vol. 360, no. 1, pp. 44–52, 2009.
View at: Publisher Site | Google Scholar
C. Serradeil-Le Gal, D. Raufaste, G. Brossard et al., “Characterization and localization of leptin receptors in the rat kidney,” FEBS Letters, vol. 404, no. 2-3, pp. 185–191, 1997.
View at: Publisher Site | Google Scholar
E. K. Jackson and P. Li, “Human leptin has natriuretic activity in the rat,” American Journal of Physiology, vol. 272, no. 3, pp. F333–F338, 1997.
View at: Google Scholar
D. Villarreal, G. Reams, and R. H. Freeman, “Effects of renal denervation on the sodium excretory actions of leptin in hypertensive rats,” Kidney International, vol. 58, no. 3, pp. 989–994, 2000.
View at: Publisher Site | Google Scholar
G. F. DiBona, “The kidney in the pathogenesis of hypertension: the role of renal nerves,” American Journal of Kidney Diseases, vol. 5, no. 4, pp. A27–A31, 1985.
View at: Google Scholar
S. Patel, D. Villarreal, A. Kundra et al., “Cardiovascular and renal actions of leptin,” Cardiac Hormones, pp. 111–127, 2008.
View at: Google Scholar
J. Bełtowski, G. Wójcicka, D. Górny, and A. Marciniak, “Human leptin administered intraperitoneally stimulates natriuresis and decreases renal medullary Na, K-ATPase activity in the rat—impaired effect in dietary-induced obesity,” Medical Science Monitor, vol. 8, no. 6, pp. BR221–BR229, 2002.
View at: Google Scholar
D. Villarreal, G. Reams, H. Samar, R. Spear, and R. H. Freeman, “Effects of chronic nitric oxide inhibition on the renal excretory response to leptin,” Obesity Research, vol. 12, no. 6, pp. 1006–1010, 2004.
View at: Google Scholar
L. Lin, R. Martin, A. O. Schaffhauser, and D. A. York, “Acute changes in the response to peripheral leptin with alteration in the diet composition,” American Journal of Physiology, vol. 280, no. 2, pp. R504–R509, 2001.
View at: Google Scholar
A. Bouloumié, T. Marumo, M. Lafontan, and R. Busse, “Leptin induces oxidative stress in human endothelial cells,” FASEB Journal, vol. 13, no. 10, pp. 1231–1238, 1999.
View at: Google Scholar
A. D. Dobrian, S. D. Schriver, T. Lynch, and R. L. Prewitt, “Effect of salt on hypertension and oxidative stress in a rat model of diet-induced obesity,” American Journal of Physiology, vol. 285, no. 4, pp. F619–F628, 2003.
View at: Google Scholar
M. Adamczak, F. Kokot, J. Chudek, and A. Wiecek, “Effect of renin-angiotensin system activation by dietary sodium restriction and upright position on plasma leptin concentration in patients with essential hypertension,” Medical Science Monitor, vol. 8, no. 7, pp. CR473–CR477, 2002.
View at: Google Scholar
G. Wolf and F. N. Ziyadeh, “Leptin and renal fibrosis,” Contributions to Nephrology, vol. 151, pp. 175–183, 2006.
View at: Publisher Site | Google Scholar
G. Wolf, S. Chen, D. C. Han, and F. N. Ziyadeh, “Leptin and renal disease,” American Journal of Kidney Diseases, vol. 39, no. 1, pp. 1–11, 2002.
View at: Google Scholar
N. Deji, S. Kume, S. I. Araki et al., “Structural and functional changes in the kidneys of high-fat diet-induced obese mice,” American Journal of Physiology, vol. 296, no. 1, pp. F118–F126, 2009.
View at: Publisher Site | Google Scholar
M. H. Gannagé-Yared, S. Khalife, M. Semaan, F. Fares, S. Jambart, and G. Halaby, “Serum adiponectin and leptin levels in relation to the metabolic syndrome, androgenic profile and somatotropic axis in healthy non-diabetic elderly men,” European Journal of Endocrinology, vol. 155, no. 1, pp. 167–176, 2006.
View at: Publisher Site | Google Scholar
K. Sharma, R. V. Considine, B. Michael et al., “Plasma leptin is partly cleared by the kidney and is elevated in hemodialysis patients,” Kidney International, vol. 51, no. 6, pp. 1980–1985, 1997.
View at: Google Scholar
L. Nordfors, F. Lönnqvist, O. Heimbürger, A. Danielsson, M. Schalling, and P. Stenvinkel, “Low leptin gene expression and hyperleptinemia in chronic renal failure,” Kidney International, vol. 54, no. 4, pp. 1267–1275, 1998.
View at: Publisher Site | Google Scholar
P. Stenvinkel, F. Lönnqvist, and M. Schalling, “Molecular studies of leptin: implications for renal disease,” Nephrology Dialysis Transplantation, vol. 14, no. 5, pp. 1103–1112, 1999.
View at: Publisher Site | Google Scholar
O. Heimbürger, F. Lönnqvist, A. Danielsson, J. Nordenström, and P. Stenvinkel, “Serum immunoreactive leptin concentration and its relation to the body fat content in chronic renal failure,” Journal of the American Society of Nephrology, vol. 8, no. 9, pp. 1423–1430, 1997.
View at: Google Scholar
F. Cumin, H.-P. Baum, M. De Gasparo, and N. Levens, “Removal of endogenous leptin from the circulation by the kidney,” International Journal of Obesity, vol. 21, no. 6, pp. 495–504, 1997.
View at: Google Scholar
K. L. Johansen, K. Mulligan, V. Tai, and M. Schambelan, “Leptin, body composition, and indices of malnutrition in patients on dialysis,” Journal of the American Society of Nephrology, vol. 9, no. 6, pp. 1080–1084, 1998.
View at: Google Scholar
P. Stenvinkel, O. Heimbürger, and F. Lönnqvist, “Serum leptin concentrations correlate to plasma insulin concentrations independent of body fat content in chronic renal failure,” Nephrology Dialysis Transplantation, vol. 12, no. 7, pp. 1321–1325, 1997.
View at: Publisher Site | Google Scholar
M. P. Fontan, A. Rodriguez-Carmona, F. Cordido, and J. Garcia-Buela, “Hyperleptinemia in uremic patients undergoing conservative management, peritoneal dialysis, and hemodialysis: a comparative analysis,” American Journal of Kidney Diseases, vol. 34, no. 5, pp. 824–831, 1999.
View at: Google Scholar
M. Bossola, L. Tazza, S. Giungi, and G. Luciani, “Anorexia in hemodialysis patients: an update,” Kidney International, vol. 70, no. 3, pp. 417–422, 2006.
View at: Publisher Site | Google Scholar
P. Stenvinkel, B. Lindholm, F. Lönnqvist, K. Katzarski, and O. Heimbürger, “Increases in serum leptin levels during peritoneal dialysis are associated with inflammation and a decrease in lean body mass,” Journal of the American Society of Nephrology, vol. 11, no. 7, pp. 1303–1309, 2000.
View at: Google Scholar
M. Odamaki, R. Furuya, T. Yoneyama et al., “Association of the serum leptin concentration with weight loss in chronic hemodialysis patients,” American Journal of Kidney Diseases, vol. 33, no. 2, pp. 361–368, 1999.
View at: Google Scholar
R. H. Mak, W. Cheung, R. D. Cone, and D. L. Marks, “Leptin and inflammation-associated cachexia in chronic kidney disease,” Kidney International, vol. 69, no. 5, pp. 794–797, 2006.
View at: Publisher Site | Google Scholar
W. Cheung, P. X. Yu, B. M. Little, R. D. Cone, D. L. Marks, and R. H. Mak, “Role of leptin and melanocortin signaling in uremia-associated cachexia,” Journal of Clinical Investigation, vol. 115, no. 6, pp. 1659–1665, 2005.
View at: Publisher Site | Google Scholar
J. Axelsson, A. R. Qureshi, O. Heimbürger, B. Lindholm, P. Stenvinkel, and P. Bárány, “Body fat mass and serum leptin levels influence epoetin sensitivity in patients with ESRD,” American Journal of Kidney Diseases, vol. 46, no. 4, pp. 628–634, 2005.
View at: Publisher Site | Google Scholar
S. C. Hung, T. Y. Tung, C. S. Yang, and D. C. Tarng, “High-calorie supplementation increases serum leptin levels and improves response to rHuEPO in long-term hemodialysis patients,” American Journal of Kidney Diseases, vol. 45, no. 6, pp. 1073–1083, 2005.
View at: Publisher Site | Google Scholar
G. Coen, P. Ballanti, M. S. Fischer et al., “Serum leptin in dialysis renal osteodystrophy,” American Journal of Kidney Diseases, vol. 42, no. 5, pp. 1036–1042, 2003.
View at: Google Scholar
F. Mallamaci, G. Tripepi, and C. Zoccali, “Leptin in end stage renal disease (ESRD): a link between fat mass, bone and the cardiovascular system,” Journal of Nephrology, vol. 18, no. 4, pp. 464–468, 2005.
View at: Google Scholar
C. Zoccali, F. Mallamaci, and G. Tripepi, “Adipose tissue as a source of inflammatory cytokines in health and disease: focus on end-stage renal disease,” Kidney International, Supplement, vol. 63, no. 84, pp. S65–S68, 2003.
View at: Google Scholar
V. Emilsson, Y. L. Liu, M. A. Cawthorne, N. M. Morton, and M. Davenport, “Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion,” Diabetes, vol. 46, no. 2, pp. 313–316, 1997.
View at: Google Scholar
S. Konstantinides, K. Schäfer, S. Koschnick, and D. J. Loskutoff, “Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity,” Journal of Clinical Investigation, vol. 108, no. 10, pp. 1533–1540, 2001.
View at: Publisher Site | Google Scholar
M. R. Sierra-Honigmann, A. K. Nath, C. Murakami et al., “Biological action of leptin as an angiogenic factor,” Science, vol. 281, no. 5383, pp. 1683–1686, 1998.
View at: Publisher Site | Google Scholar
P. Singh, M. Hoffmann, R. Wolk, A. S. M. Shamsuzzaman, and V. K. Somers, “Leptin induces C-reactive protein expression in vascular endothelial cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 9, pp. e302–e307, 2007.
View at: Publisher Site | Google Scholar
A. Romero-Corral, J. Sierra-Johnson, F. Lopez-Jimenez et al., “Relationships between leptin and C-reactive protein with cardiovascular disease in the adult general population,” Nature Clinical Practice Cardiovascular Medicine, vol. 5, no. 7, pp. 418–425, 2008.
View at: Publisher Site | Google Scholar
M. Karmazyn, D. M. Purdham, V. Rajapurohitam, and A. Zeidan, “Leptin as a cardiac hypertrophic factor: a potential target for therapeutics,” Trends in Cardiovascular Medicine, vol. 17, no. 6, pp. 206–211, 2007.
View at: Publisher Site | Google Scholar
V. Rajapurohitam, X. T. Gan, L. A. Kirshenbaum, and M. Karmazyn, “The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes,” Circulation Research, vol. 93, no. 4, pp. 277–279, 2003.
View at: Publisher Site | Google Scholar
K. Selthofer-Relatić, R. Radić, V. Vizjak et al., “Hyperleptinemia—non-haemodynamic risk factor for the left ventricular hypertrophy development in hypertensive overweight females,” Collegium Antropologicum, vol. 32, no. 3, pp. 681–685, 2008.
View at: Google Scholar
Y. Umemoto, K. Tsuji, F. C. Yang et al., “Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cells,” Blood, vol. 90, no. 9, pp. 3438–3443, 1997.
View at: Google Scholar
G. Paolisso, M. R. Tagliamonte, M. Galderisi et al., “Plasma leptin level is associated with myocardial wall thickness in hypertensive insulin-resistant men,” Hypertension, vol. 34, no. 5, pp. 1047–1052, 1999.
View at: Google Scholar
F. Leyva, S. D. Anker, K. Egerer, J. C. Stevenson, W. J. Kox, and A. J. S. Coats, “Hyperleptinaemia in chronic heart failure. Relationships with insulin,” European Heart Journal, vol. 19, no. 10, pp. 1547–1551, 1998.
View at: Publisher Site | Google Scholar
D. M. Purdham, V. Rajapurohitam, A. Zeidan, C. Huang, G. J. Gross, and M. Karmazyn, “A neutralizing leptin receptor antibody mitigates hypertrophy and hemodynamic dysfunction in the postinfarcted rat heart,” American Journal of Physiology, vol. 295, no. 1, pp. H441–H446, 2008.
View at: Publisher Site | Google Scholar
V. Rajapurohitam, S. Javadov, D. M. Purdham, L. A. Kirshenbaum, and M. Karmazyn, “An autocrine role for leptin in mediating the cardiomyocyte hypertrophic effects of angiotensin II and endothelin-1,” Journal of Molecular and Cellular Cardiology, vol. 41, no. 2, pp. 265–274, 2006.
View at: Publisher Site | Google Scholar
AI. Nagae, M. Fujita, H. Kawarazaki, H. Matsui, K. Ando, and T. Fujita, “Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in obesity-induced hypertension,” Circulation, vol. 119, no. 7, pp. 978–986, 2009.
View at: Publisher Site | Google Scholar
Y. Abe, K. Ono, T. Kawamura et al., “Leptin induces elongation of cardiac myocytes and causes eccentric left ventricular dilatation with compensation,” American Journal of Physiology, vol. 292, no. 5, pp. H2387–H2396, 2007.
View at: Publisher Site | Google Scholar
K. R. Mcgaffin, B. Zou, C. F. Mctiernan, and C. P. O'donnell, “Leptin attenuates cardiac apoptosis after chronic ischaemic injury,” Cardiovascular Research, vol. 83, no. 2, pp. 313–324, 2009.
View at: Publisher Site | Google Scholar
L. A. Barouch, D. E. Berkowitz, R. W. Harrison, C. P. O'Donnell, and J. M. Hare, “Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice,” Circulation, vol. 108, no. 6, pp. 754–759, 2003.
View at: Publisher Site | Google Scholar
P. Tajmir, R. B. Ceddia, R. K. Li, I. R. Coe, and G. Sweeney, “Leptin increases cardiomyocyte hyperplasia via extracellular signal-regulated kinase- and phosphatidylinositol 3-kinase-dependent signaling pathways,” Endocrinology, vol. 145, no. 4, pp. 1550–1555, 2004.
View at: Publisher Site | Google Scholar
M. W. Nickola, L. E. Wold, P. B. Colligan, G. J. Wang, W. K. Samson, and J. Ren, “Leptin attenuates cardiac contraction in rat ventricular myocytes role of NO,” Hypertension, vol. 36, no. 4, pp. 501–505, 2000.
View at: Google Scholar
J. D. Luo, G. S. Zhang, and M. S. Chen, “Leptin and cardiovascular diseases,” Drug News and Perspectives, vol. 18, no. 7, pp. 427–431, 2005.
View at: Publisher Site | Google Scholar
N. A. Tritos, W. J. Manning, and P. G. Danias, “Role of leptin in the development of cardiac hypertrophy in experimental animals and humans,” Circulation, vol. 109, no. 7, p. e67, 2004.
View at: Google Scholar
P. C. Schulze, J. Kratzsch, A. Linke et al., “Elevated serum levels of leptin and soluble leptin receptor in patients with advanced chronic heart failure,” European Journal of Heart Failure, vol. 5, no. 1, pp. 33–40, 2003.
View at: Publisher Site | Google Scholar

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Copyright © 2011 Shilpa Kshatriya 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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