Vascular endothelial dysfunction: A tug of war in diabetic nephropathy?

Available online at

www.sciencedirect.com Biomedicine & Pharmacotherapy 63 (2009) 171e179

Review

Vascular endothelial dysfunction: A tug of war in diabetic nephropathy? Pitchai Balakumar a,*, Vishal Arvind Chakkarwar a, Pawan Krishan b, Manjeet Singh a b

a Cardiovascular Pharmacology Division, ISF College of Pharmacy, Moga 142 001, Punjab, India Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147 002, Punjab, India

Received 19 July 2008; accepted 19 August 2008 Available online 27 September 2008

Abstract Vascular endothelium regulates vascular tone and maintains free flow of blood in vessels. Vascular endothelial dysfunction (VED) results in reduced activation of endothelial nitric oxide synthase (eNOS), reduced generation and bioavailability of nitric oxide (NO) and increased production of reactive oxygen species (ROS). The eNOS uncoupling in VED leads to eNOS mediated production of ROS that further damage the endothelial cells by upregulating the proinflammatory mediators and adhesion molecules. VED has been associated in the pathogenesis of hypertension, atherosclerosis, coronary artery diseases, diabetes mellitus and nephropathy. Diabetes is a chronic metabolic disorder characterized by hyperglycemia followed by micro and macrovascular complications. A correlation between diabetes and VED has been demonstrated in various studies. The downregulation of eNOS in diabetes has been noted to accelerate diabetic nephropathy. Moreover, various endogenous vasoconstrictors are also upregulated in diabetic nephropathy. VED has been shown to be involved in diabetic nephropathy by inducing nodular glomerulosclerosis followed by glomerular basement membrane thickness and mesangial expansion, which ultimately decline glomerular filtration rate (GFR). Thus it is suggested that diabetes-induced VED could be one of the culprits involved in the pathogenesis of diabetic nephropathy. Ó 2008 Elsevier Masson SAS. All rights reserved. Keywords: Endothelium; Vascular endothelial dysfunction; Diabetes; Nephropathy; Target sites

1. Introduction Endothelium is an interior covering of blood vessels. The biological functions of endothelium are numerous and it regulates vascular tone and maintenance of free flow of blood in vessels [1]. VED results in reduced activation of endothelial eNOS and increased production of ROS, which account for reduced synthesis and bioavailability of NO, respectively [1e 4]. The deregulation of endothelial function upregulates the expression of procoagulant, prothrombotic and proinflammatory mediators, which are implicated in the pathogenesis of various disorders such as hypertension [4], * Corresponding author. Cardiovascular Pharmacology Division, ISF College of Pharmacy, Institute of Pharmaceutical Sciences and Drug Research, Moga 142 001, India. Tel.: þ91 9815557265; fax: þ91 1636236564. E-mail address: [email protected] (P. Balakumar). 0753-3322/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.biopha.2008.08.008

atherosclerosis [5,6], coronary artery diseases [2] and diabetic nephropathy [7e11]. Diabetes is a metabolic disorder characterized by hyperglycemia, which induces micro- and macrovascular complications [12]. A correlation between diabetes and VED has been noted in various studies [7,9,10,13,14]. The increased serum concentration of advanced glycation end products (AGEs) in patients with diabetes has been associated with dysfunction of vascular endothelium [9]. High concentration of glucose has been noted to induce endothelial apoptotic cell death by activating the baxecaspase proteases pathway [6,15]. It has been demonstrated that hyperglycemia scavenges NO and induces VED, which ultimately results in nephropathy [9,11,16,17]. VED increases the deposition of the extracellular matrix that leads to glomerulosclerosis and progressive decline in the glomerular filtration rate to produce nephropathy [8,16]. The present review delineates the relationship between VED and diabetic nephropathy.

172

P. Balakumar et al. / Biomedicine & Pharmacotherapy 63 (2009) 171e179

2. Concept of vascular endothelial dysfunction Endothelium is an inner layer of blood vessels made up of polygonal epithelial cells that extend continuously over the luminal surface of the entire vasculature [18]. The healthy endothelium regulates vascular tone and exerts anticoagulant [19], antithrombotic [20], antiplatelet [19] and fibrinolytic [21] properties. Endothelium is a multifunctional organ and it regulates the release of endothelium derived relaxing factors (EDRF), endothelium derived contracting factors (EDCF), endothelium derived hyperpolarizing factors (EDHF) [1,5], inflammatory mediators such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM1), von Willebrand factor, nuclear factor kappa-B (NF-kB) and various growth factors like vascular endothelial growth factors (VEGF), basic fibroblast growth factors (bFGF), platelet derived growth factors (PDGF) and transforming growth factor-b (TGF-b) [7,21,22]. The vasodilatory substances released by the endothelium are NO, prostacyclin (PGI2) and bradykinin (BK) whereas vasoconstrictors are thromboxane A2 (TXA2), endothelin-1 (ET-1), angiotensin II (ang-II) and prostaglandin H2 (PGH2) [21,22]. The most important vasodilatory substance released by the endothelium is NO, which is generated from the amino acid L-arginine by the enzyme known as eNOS in the presence of cofactors such as flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), tetrahydrobiopterin (BH4) and calmodulin [23]. NO released in the vascular lumen binds with the heme moiety of soluble guanylate cyclase and thereby increases the production of intracellular cyclic 30 e50 guanosine monophosphate (cGMP), which relaxes the smooth muscle [12]. VED may be defined as an impairment in endothelium dependent vasodilation and alteration in the normal properties of endothelium, during which endothelium fails to maintain the vascular tone [5]. VED has been considered to play a pathological role in the initiation and progression of various cardiovascular disorders such as atherosclerosis, hypertension and coronary artery diseases [4e6]. Oxidative stress plays an important role in the pathogenesis of VED [4]. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase derived ROS such as superoxide anion (O2), hydrogen peroxide (H2O2), hydroxyl radical (OH) and peroxynitrite (OONO) damage the endothelial cells by upregulating proinflammatory mediators, adhesion molecules and inducing apoptosis [21,24]. The VED often results in eNOS uncoupling, a condition that leads to eNOS mediated production of superoxides and peroxynitrite, possibly due to mismatch between eNOS and its cofactors [23]. It has been noted that uncoupling of essential cofactors like BH4 with eNOS results in decreased NO production and increased formation of ROS [25]. Vasoconstrictor peptides such as ang-II, ET-I and arginine vasopressin (AVP) are noted to be upregulated in VED [26e28]. Ang-II mediated activation of janus kinase (JAK) inhibits the phosphotidyl inositol 3kinase (PI3-K)/Akt pathway resulting in reduced activity of eNOS and reduced production of NO [29,30]. AVP increases expression of VEGF and acts as vasoconstrictor via activation of Rho-kinase [27,31]. Urotensin-II, an endogenous

vasoconstrictor, has been suggested to be involved in the pathogenesis of VED [32]. Urotensin-II decreased endothelium dependent relaxation by increasing the activity of NADPH oxidase and plasminogen activator inhibitor-1 (PAI1) [33]. The overexpression of urotensin-II in endothelial cells accelerates VED by increasing the expression of type 1 collagen and formation of ROS [32,33]. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of eNOS and has been noted to decrease the generation of NO [34]. ADMA is an amino acid synthesized from methylated arginine residues by the action of enzyme protein arginine methyltransferase (PRMT) [35] and ADMA is inactivated by dimethylarginine dimethylaminohydrolase (DDAH) [36]. It has been suggested that downregulation of DDAH activity is one of the key factors for endothelial dysfunction that causes accumulation of ADMA, which consequently inhibits the production of NO and promotes the release of proatherogenic mediators such as ICAM-1, VCAM-1, vWF and NF-kB [20,34,36,37]. The caveolin gene family comprises three isoforms such as caveolin-1, caveolin-2 and caveolin-3, which are present in invaginations (50e100 nm in size) of plasma membrane known as caveolae [22]. Caveolin-1 is predominantly expressed in endothelial cells, where it is believed to play a major role in the regulation of endothelial function by negatively regulating eNOS [38]. The overexpression of caveolin-1 inhibits the activation of eNOS and consequently reduces the production of NO by binding with calmodulin, an essential cofactor for eNOS activation [22,39]. The C-reactive protein (CRP) level is increased in response to cytokineinduced tissue injury, infection and inflammation [40]. The elevated level of CRP impairs the generation and bioavailability of NO by downregulating eNOS and increasing the generation of NADPH oxidase mediated ROS [41,42]. The adipocyte releases a number of bioactive molecules such as leptin, resistin, adiponectin, tumor necrosis factor-a (TNF-a) and PAI-1. Leptin, a peptide hormone produced by white adipose tissue, is primarily involved in the regulation of food intake and energy expenditure [43,44]. Leptin was noted to positively correlate with plasma levels of VCAM-1, proinflammatory mediators and increase the generation of ROS in endothelial cells [43] and thereby may play a role in the pathogenesis of VED. Resistin, a novel adipokine, has been implicated in VED due to its pathological role on endothelium such as upregulation of VCAM-1, ET-1 and generation of superoxides and followed by inactivation of eNOS [45e47]. Rho-kinase, a serine threonine kinase is expressed in endothelial cells. Activation of Rho-kinase inhibits myosin light chain phosphatase to increase the vascular tone and thus is involved in the pathogenesis of hypertension and coronary vasospasm [48]. Rho-kinase is a negative regulator of eNOS and thus suppresses NO generation [49]. Moreover, Rhokinase has been implicated in the pathogenesis of VED and cardiac hypertrophy [50,51]. Apelin is an endogenous ligand for G-protein coupled APJ receptor and is widely expressed in various organs such as heart, kidney, adipose tissue and endothelium [52]. Apelin phosphorylates Akt and raises intracellular calcium, both of which activates eNOS and thus

P. Balakumar et al. / Biomedicine & Pharmacotherapy 63 (2009) 171e179

ADMA

Leptin

Resistin CRP

Ang-II, ET-I, Urotensin-II, AVP and Rho-kinase

Vasoconstriction

173

Oxidative Stress

Upregulation of Proinflammatory Mediators

eNOS

Apelin

Caveolin

BH4 NO Adiponectin

Vascular Endothelial Dysfunction

Fig. 1. Novel target sites in the pathogenesis of vascular endothelial dysfunction. Ang-II, angiotensin-II; ET-1, endothelin-1; AVP, arginine vasopressin; ADMA, asymmetric dimethylarginine; CRP, c-reactive protein; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; BH4, tetrahydrobiopterin.

promotes the generation of NO [53]. Adiponectin is an adipocyte (fat cell) derived circulating plasma protein with insulin-sensitizing metabolic effects and vascular protective properties [54]. Interestingly, low plasma adiponectin concentration was noted in patients with obesity, coronary artery disease (CAD) and type 2 diabetes with macroangiopathy. It has been noted that adiponectin suppressed the endothelial expression of adhesion molecules, the proliferation of vascular smooth muscle cells and the transformation of macrophage to foam cells by upregulating eNOS mediated NO production and downregulating ROS generation [55]. The various signaling molecules involved in the pathogenesis of VED are shown in Fig. 1.

regulatory element-binding protein (SREBP), which is responsible for increasing the synthesis of triglycerides and cholesterol in the kidney, that are associated with increased expression of TGF-b, VEGF, extracellular matrix proteins, type IV collagen and fibronectin resulting in glomerular hypertrophy. Further, SREBP stimulates podocyte injury, glomerulosclerosis and tubulointerstitial fibrosis to produce nephropathy [58,59]. The pathogenic role of SREBP-1 in diabetic nephropathy is shown in Fig. 2. Hyperglycemia induces caspase-3 mediated apoptotic cell death in endothelial cells [6]. In addition, diabetes upregulates the generation of

Diabetes Mellitus

3. Vascular endothelial dysfunction and diabetic nephropathy In diabetes, hyperglycemia causes micro and macrovascular complications [12]. Diabetic nephropathy is also known as KimmelstieleWilson syndrome and it was discovered in 1936 by Clifford Wilson and Paul Kimmelstiel. The final stage of nephropathy is called end-stage renal disease (ESRD) and is a leading cause of morbidity and mortality in diabetic patients. Diabetic nephropathy is defined as partial loss of kidney function followed by nephrotic syndrome and glomerulosclerosis. Nephropathy is characterized by persistent elevated albuminuria, declined GFR, elevated arterial blood pressure and fluid retention (oedema) [56,57]. Although several factors may mediate the development and progression of diabetic nephropathy, hyperlipidemia has been considered to be an independent risk factor and major determinant of progression of nephropathy in patients with diabetes. The experimental evidence suggests that hyperlipidemia may mediate renal injury by increasing the expression of sterol

Hyperglycemia

SREBP -1

Free Fatty Acid TGF-β and VEGF -

Matrix Protein accumulation, Glomerulosclerosis and Tubulointerstitial Fibrosis Proteinuria

Diabetic Nephropathy

Fig. 2. Role of SREBP1 in diabetic nephropathy. SREBP 1, sterol regulatory element-binding protein 1; TGF-b, transforming growth factor; VEGF, vascular endothelial growth factors.

174

P. Balakumar et al. / Biomedicine & Pharmacotherapy 63 (2009) 171e179

nephropathy [67]. AVP stimulates mesangial cell proliferation, glomerular hypertrophy and upregulates ET-1 secretion from mesangial cells leading to glomerular remodeling [31]. In diabetic patients, serum concentration of urotensin-II has been noted to be elevated [68], while treatment with palosuran, an urotensin-II receptor antagonist attenuated diabetic nephropathy [69]. ADMA is involved in peritubular capillary loss and tubulointerstitial fibrosis and thereby contributes to the progression of nephropathy [70]. Caveolin-1 gets upregulated in acute renal failure and contributes to the severity of tubulointerstitial fibrosis resulting in obstructive nephropathy [71,72]. Increased serum level of CRP is a marker of nephrotic syndrome [73]. Downregulation of eNOS by CRP exerted proinflammatory effects in endothelium and mesangial cells by inducing monocyte chemoattractant protein-1 (MCP-1) and NF-kB activation [74]. In obese and diabetic patients, the incidence of renal glomerulosclerosis was found to be high

AGEs, which contributes to VED [9]. Hyperglycemia alters endothelial glycocalyx permeability resulting in changes in the functional properties of capillaries [60]. Moreover, the expression and activity of eNOS is downregulated through glucose mediated production of ROS in diabetes [61,62]. The ROS thus generated during diabetes play a major role in the pathogenesis of hyperglycemic injury and alter intraglomerular hemodynamics in nephropathy [63]. The mechanism involved in diabetes-induced VED is summarized in Fig. 3. Various endogenous modulators such as ang-II, ET-I, AVP, urotensin-II, ADMA, caveolin, CRP, leptin, resistin and Rho-kinase are upregulated in VED [26,34,42,43,46,51,64] whereas adiponectin and apelin are downregulated in VED [65,66]. Ang-II stimulates the release of VEGF and develops proteinuria in diabetic nephropathy [60,64,66]. ET-I plays an important role in nephropathy and treatment with LU 135252, an ETA antagonist reduced proteinuria in rats with diabetic

Diabetes

Hyperglycemia

Activation of PKC and Polyol Pathway, Glucose Autooxidation

AGEs

Dowregulation of BH4, PGI2 and Bradykinin

Upregulation of PGH2 TXA2 ET-1 and Ang-II

Increased Oxidative Stress

Upregulation of ICAM-I VCAM-I E-selectin vWF and PDGF

Increase LDL VLDL and Decrease HDL

Dyslipidemia

eNOS

NO

Vascular Endothelial Dysfunction

Fig. 3. Mechanisms involved in diabetes-induced vascular endothelial dysfunction. PKC, protein kinase C; AGEs, advanced glycation end products; BH4, tetrahydrobiopterin; PGI2, prostacyclin I2; PGH2, prostaglandin H2; TXA2, thromboxane A2; ET-1, endothelin-1; Ang-II, angiotensin II; ICAM-1, intracellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; vWF, von Willebrand factor; PDGF, platelet derived growth factor; LDL, low density lipoprotein; VLDL, very low density lipoprotein; HDL, high density lipoprotein; eNOS, endothelial nitric oxide synthase; NO, nitric oxide.

P. Balakumar et al. / Biomedicine & Pharmacotherapy 63 (2009) 171e179

due to increased concentration of serum leptin. Leptin plays a pathogenic role in nephropathy associated with obesity by inducing glomerular cell hypertrophy [75]. Resistin concentration has been noted to be increased in patients with nephropathy and is associated with reduced glomerular filtration rate with increased urine albumin:creatinine ratio [76e78]. Rho-kinase is involved in renal damage caused by ang-II through upregulation of proinflammatory and profibrotic mediators such as TNF-a and MCP-1 [79]. The pathogenic role of Rho-kinase was confirmed by the fact that inhibition of Rho-kinase by fasudil produced renoprotective effects in diabetic rats by inhibiting extracellular matrix gene expression, monocyte/macrophage infiltration, oxidative stress and upregulating eNOS [80,81]. Moreover, Rho-kinase inhibition was shown to attenuate the process of hypertensive glomerulosclerosis [82]. The overexpression of JAK in diabetic nephropathy is associated with excessive proliferation and growth of mesangial cells that occlude glomerular capillaries and provoke progressive thickening of glomerular and tubular basement membranes through podocyte inflammation [30,83]. Apelin and adiponectin get downregulated in diabetic nephropathy [84]. Apelin exerts beneficial effects in diabetic

175

nephropathy by activating eNOS and regulating intrarenal arterial tone. Further, apelin modulates abnormal aortic vascular tone in response to ang-II by activating Akt that further activates eNOS [53]. Adiponectin is inversely associated with inflammatory markers such as fibrinogen, ICAM-1, E-selectin and CRP and increased serum adiponectin provides protection against vascular diseases [84]. The mechanism involved in VED-induced diabetic nephropathy is shown in Fig. 4. 4. Perspectives in the treatment of diabetic nephropathy ACE inhibitors such as captopril, lisinopril, quinapril and fosinopril are currently employed to treat diabetic nephropathy. ACE inhibitors activate eNOS, increase bioavailability of NO and inhibit synthesis of ang-II [85]. Lisinopril inhibits the formation of TGF-b and tubulointerstitial fibrosis in patients with diabetic nephropathy [86]. Fosinopril reduces proteinuria. glomerular hypertrophy and tubulointerstitial fibrosis in experimental diabetic nephropathy [87]. Quinapril reduces proteinuria, cholesterol levels, glomerular lesions and podocyte damage in diabetic nephropathy [88]. Angiotensin-II AT1

Vascular Endothelial Dysfunction

VEGF

Cytokines (IL-6 and TGF-β)

Glomerulosclerosis and Podocyte Differentiation

Expansion of Mesangial Matrix

Decrease in Renal Flow, Increase in Intra-Glomerular Hydrostatic Pressure and Arteriolar Resistance, Alteration in Intra Renal Hemodynamics

Occlusion of Glomerular Capillaries Glomerular Basement Thickness Podocyte Inflammation

Tubulointerstitial Fibrosis Glomerular Hypertrophy

Collagen Accumulation

Decline in Glomerular Filtration Rate

Diabetic Nephropathy

Fig. 4. Mechanisms involved in VED-induced nephropathy in diabetes. VEGF, vascular endothelial growth factors; IL-6, interlukin-6; TGF-b, transforming growth factor b.

P. Balakumar et al. / Biomedicine & Pharmacotherapy 63 (2009) 171e179

176

receptor blockers like candesartan and telmisartan have been noted to attenuate diabetic nephropathy by reducing proteinuria [89,90]. Endothelin-A (ETA) receptor antagonists like ABT-627 have been noted to reduce proteinuria in experimental diabetic nephropathy [91]. Treatment with S18886, a thromboxane receptor antagonist significantly attenuated experimental diabetic nephropathy by reducing the expression of TGF- b, extracellular matrix protein and decreasing microalbuminuria [92]. Palosuran, a novel and selective urotensin-II receptor blocker was noted to reduce albuminuria in renal disease [69]. Activation of peroxisome proliferatoractivated receptor-a (PPAR-a) by fenofibrate produced renoprotective effect by suppressing renal PAI-1 in experimental diabetic nephropathy [93]. PPAR-g agonists such as pioglitazone and rosiglitazone significantly reduced glomerulosclerosis and tubulointerstitial fibrosis in patients with diabetic nephropathy [94,95]. In addition, pioglitazone markedly reduced glomerular hypertrophy, mesangial expansion and urinary albumin excretion in patients with diabetic nephropathy [95]. Recently it has been suggested that suppression of the Rho-kinase pathway could be a novel strategy to treat diabetic nephropathy. This contention was proved by the fact that treatment with fasudil, a selective inhibitor of Rho-kinase attenuated experimental diabetic nephropathy by downregulating TGF-b and reducing ROS formation [81]. Inhibition of HMG-CoA-reductase by statins like atorvastatin, pravastatin and cerivastatin was noted to activate eNOS, maintain GFR and renal cortical blood flow and consequently reduce glomerular lesion [96e98]. Benfotiamine, a transketolase activator, has been noted to activate eNOS, decrease ROS formation, reduce proteinuria and inhibit hyperfiltration in patients with diabetic nephropathy [99]. Resveratrol, a polyphenolic phytoalexin present in red wine attenuated renal dysfunction by reducing proteinuria and ROS formation in rats with diabetic nephropathy [100]. The bioflavonoid quercetin has been noted to reduce proteinuria and ROS formation in diabetic rats with nephropathy [101]. Imatinib, a PDGF receptor antagonist improved renal function in rats with kidney dysfunction [102]. Various herbal drugs such as ginger and Vigna angularis were shown to have protective effects in diabetic nephropathy due to their potent antioxidant Table 1 Potential target sites in diabetic nephropathy Sr. no.

Targets

Interventions

1

Inhibition of ACE

2 3 4 5 6 7 8

Blockade of AT1 receptor Blockade of ETA receptor Blockade of thromboxane receptor Blockade of urotensin-II receptor Activation of PPAR-a Activation of PPAR-g Inhibition of HMG-coA-reductase

9 10 11

Inhibition of Rho-kinase Activation of transketolase Inhibition of PDGF

Captopril, lisinopril, quinapril and fosinopril Candisartan and telmisartan ABT-627 S18886 Palosuran Fenofibrate and clofibrate Pioglitazone and rosiglitazone Atorvastatin, pravastatin and cerivastatin Fasudil Benfotiamine Imatinib

properties [103,104]. Various potential target sites in diabetic nephropathy are shown in Table 1. On the basis of this discussion, it may be suggested that the above-mentioned drugs may have improved renal function in nephropathy due to their properties of protecting the function of vascular endothelium. 5. Conclusion VED has been revealed to be involved in diabetic nephropathy by inducing nodular glomerulosclerosis, mesangial expansion and decreasing the glomerular filtration rate. Diabetes-induced VED could be one of the culprits implicated in the pathogenesis of diabetic nephropathy since the mediators of endothelial dysfunction such as ang-II, ET-I, AVP, urotensin-II, ADMA, caveolin, CRP, leptin, resistin and Rhokinase are getting upregulated and actively involved in nephropathy. Thus, it may be suggested that diabetes-induced VED upregulates various mediators that ultimately lead to nephropathy. The pharmacological agents that improve the function of vascular endothelium may open a new vista for treating patients with diabetic nephropathy.

Acknowledgements We wish to express our gratitude to Shri. Parveen Garg, Honorable Chairman, ISF College of Pharmacy, Moga, Punjab, India, for his praiseworthy inspiration and support for this study.

References [1] Escandon JC, Cipolla M. Diabetes and endothelial dysfunction: a clinical perspective. Endocr Rev 2001;22:36e52. [2] Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001;104:2673e703. [3] Laursen JB, Boesgaard S, Trautner S, Rubin I, Poulsen HE, Aldershvile J. Endothelium-dependent vasorelaxation is inhibited by in vivo depletion of vascular thiol levels: role of endothelial nitric oxide synthase. Free Radic Res 2001;35:387e94. [4] Ulker S, McKeown P, Bayraktutan U. Vitamins reverse endothelial dysfunction through regulation of eNOS and NADPH oxidase activities. Hypertension 2003;41:534e41. [5] Coen AD, Stehouwer A. Endothelial dysfunction in diabetes nephropathy: state of the art and potential significance for non diabetic renal disease. Nephrol Dial Transplant 2004;19:778e81. [6] Nakagami H, Kaneda Y, Ogihara T, Morishita R. Endothelial dysfunction in hyperglycemia as a trigger of atherosclerosis. Curr Diabetes Rev 2005;1:59e63. [7] Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, et al. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 2001;88:14e22. [8] Goligorsky MS, Chen J, Brodsky S. Endothelial cell dysfunction leading to diabetic nephropathy: focus on nitric oxide. Hypertension 2001;37:744e8. [9] Tan KCB, Chow WS, Victor HG, Metz C, Bucala R, Karen S, et al. Advanced glycation end products and endothelial dysfunction in type 2 diabetes. Diabetes Care 2002;25:1055e9.

P. Balakumar et al. / Biomedicine & Pharmacotherapy 63 (2009) 171e179 [10] Thorand B, Baumert J, Chambless L, Meisinger C, Kolb H, Doring A, et al. Elevated markers of endothelial dysfunction predict type 2 diabetes mellitus in middle-aged men and women from the general population. Arterioscler Thromb Vasc Biol 2006;26:398e412. [11] Nakagawa T, Sato W, Glushakova W, Heinig M, Clarke T, Thompson M, et al. Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. J Am Soc Nephrol 2007; 18:539e50. [12] Bayraktutan U. Free radicals, diabetes and endothelial dysfunction. Diabetes Obes Metab 2002;4:224e38. [13] Song Y, Maanson JE, Tinker L, Rifai N, Cook NR, Frank B, et al. Circulating levels of endothelial adhesion molecules and risk of diabetes in an ethnically diverse cohort of women. Diabetes 2007;56: 1898e904. [14] Kelly RT, Ruane-O’Hora T, Noble MIM, Drake-Holland AJ, Snow HM. Differential inhibition by hyperglycaemia of shear stress- but not acetylcholine-mediated dilatation in the iliac artery of the anaesthetized pig. J Physiol 2006;5731:133e45. [15] Nakagami H, Morishita R, Yamamoto K, Yoshimura S, Taniyama Y, Aoki M, et al. Phosphorylation of p38 mitogen-activated protein kinase downstream of bax-caspase-3 pathway leads to cell death induced by high D-glucose in human endothelial cells. Diabetes 2001;50:1472e81. [16] Futrakul N, Panichakul T, Sirisinha S, Futrakul P, Siriviriyaku P. Glomerular endothelial dysfunction in chronic kidney disease. Ren Fail 2004;26:259e64. [17] Zhao HJ, Wang S, Cheng H, Zhang Z, Takahashi T, Fogo AB, et al. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J Am Soc Nephrol 2006;17:2664e9. [18] Jindal S, Singh M, Balakumar P. Effect of bis (maltolato) oxovanadium (BMOV) in uric acid and sodium arsenite-induced vascular endothelial dysfunction in rats. Int J Cardiol 2008;128:383e91. [19] Zhihong Y, Ming X. Recent advances in understanding endothelial dysfunction in atherosclerosis. Clin Med Res 2005;4:53e65. [20] Mysliwiec M, Borawski J, Naumnikn B, Rydzewska RA. Endothelial dysfunction, atherosclerosis and thrombosis in uremia e possibilities of intervention. Rocz Akad Med Bialymst 2004;49:151e6. [21] Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol 2004;15:1983e92. [22] Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation 2004;109:III27e32. [23] Yokoyama M, Hirata KI. Endothelial nitric oxide synthase uncoupling: is it a physiological mechanism of endothelium-dependent relaxation in cerebral artery? Cardiovasc Res 2007;73:8e9. [24] Clempus RE, Griendling KK. Reactive oxygen species signaling in vascular smooth muscle cells. Cardiovasc Res 2006;71:216e25. [25] Wang X, Hattori Y, Satoh H, Iwata C, Banba N, Monden T, et al. Tetrahydrobiopterin prevents endothelial dysfunction and restores adiponectin levels in rats. Eur J Pharmacol 2006;555:48e53. [26] d’Uscio LV, Shaw S, Barton M, Luscher TF. Losartan but not verapamil inhibits angiotensin-II-induced tissue endothelin-I increase role of blood pressure and endothelial function. Hypertension 2006;31:1305e10. [27] Cavarape A, Baure J, Bartoli E, Endlich K, Parekh. Effects of angiotensin II, arginine vasopressin and thromboxane A2 in renal vascular bed: role of Rho-kinase. Nephrol Dial Transplant 2003;18:1764e9. [28] Masaki T, Sawamura T. Endothelin and endothelial dysfunction. Proc Jpn Acad 2006;82:17e24. [29] Boo YC, Jo H. Flow-dependent regulation of endothelial nitric oxide synthase: role of protein kinase. Am J Physiol Cell Physiol 2003;285: C499e508. [30] Marrero MB, Berceli AK, Stern DM, Eaton DC. Role of the JAK/STAT signaling pathway in diabetic nephropathy. Am J Physiol Renal Physiol 2006;290:F762e8. [31] Tahara A, Tsukada J, Tomura Y, Suzuki T, Yatsu T, Shibasaki M. Vasopressin stimulates the production of extracellular matrix by cultured rat mesangial cells. Clin Exp Pharmacol Physiol 2007;35: 586e93. [32] Maguire JJ, Davenport AP. Is urotensin-II the new endothelin? Br J Pharmacol 2002;137:579e88.

177

[33] Watanabe T, Kanome T, Miyazaki A, Katagiri T. Human urotensin II as a link between hypertension and coronary artery disease. Hypertens Res 2006;29:375e87. [34] Cooke JP. Does ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol 2000;20:2032e7. [35] Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine: dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol 2004;24:1e9. [36] Jiang DJ, Jia SJ, Yan J, Zhou Z, Yuan Q, Li YJ. Involvement of DDAH/ADMA/NOS pathway in nicotine-induced endothelial dysfunction. Biochem Biophys Res Commun 2006;349:683e93. [37] Boger RH. Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the ‘‘L-arginine paradox’’ and acts as a novel cardiovascular risk factor. J Nutr 2004;134:2842Se7S. [38] Peterson TE, Kleppe LS, Caplice NM, Pan S, Mueske CS, Simari RD. The regulation of caveolin expression and localization by serum and heparin in vascular smooth muscle cells. Communication 1999;265: 722e7. [39] Zuo L, Ushio-Fukai M, Ikeda S, Hilenski L, Patrushev N, Alexander RW. Caveolin-1 is essential for activation of Rac1 and NAD(P)H oxidase after angiotensin II type 1 receptor stimulation in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2005;25:1824e30. [40] Schwedler SB, Kuhlencordt PJ, Ponnuswamy PP, Hatiboglu G, Quaschning T, Widder J, et al. Native C-reactive protein induces endothelial dysfunction in ApoE/ mice: implications for iNOS and reactive oxygen species. Atherosclerosis 2007;195:e76e84. [41] Ratnam S, Mookerjea S. The regulation of superoxide generation and nitric oxide synthesis by C-reactive protein. Immunology 1998;94: 560e8. [42] Singh U, Devaraj S, Vivar JV, Jialal I. C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling. J Mol Cell Cardiol 2007;43:780e91. [43] Bouloumie A, Marumo T, Lafontan M, Busse R. Leptin induces oxidative stress in human endothelial cells. FASEB J 1999;13:1231e8. [44] Beltowski J. Leptin and atherosclerosis. Atherosclerosis 2006;189: 47e60. [45] Verma S, Li SH, Wang CH, Fedak PWM, Li RK, Weisel RD, et al. Resistin promotes endothelial cell activation: further evidence of adipokineeendothelial interaction. Circulation 2003;108:736e40. [46] Kougias P, Chai H, Lin PH, Lumsden AB, Yao Q, Chen C. Adipocytederived cytokine resistin causes endothelial dysfunction of porcine coronary arteries. J Vasc Surg 2005;41:691e8. [47] Dick GM, Katz PS, Farias M, Morris M, James J, Knudson JD, et al. Resistin impairs endothelium-dependent dilation to bradykinin but not acetylcholine, in the coronary circulation. Am J Physiol Heart Circ Physiol 2006;291:H2997e3002. [48] Balakumar P, Kaur T, Singh M. Potential target sites to modulate vascular endothelial dysfunction: current perspectives and future directions. Toxicology 2008;245:49e64. [49] Lohn M, Steioff K, Bleich M, Busch AE, Ivashchenko Y. Inhibition of Rho-kinase stimulates nitric oxide dependent vasorelaxation. Eur J Pharmacol 2005;507:179e86. [50] Balakumar P, Singh M. Different role of rho-kinase in pathological and physiological cardiac hypertrophy in rats. Pharmacology 2006;78: 91e7. [51] Balakumar P, Koladiya RU, Ramasamy S, Rathinavel A, Singh M. Pharmacological interventions to prevent vascular endothelial dysfunction: future directions. J Health Sci 2008;54:1e16. [52] Tatemoto K, Takayama K, Zou MX, Kumaki I, Zhang W, Kumano K, et al. The novel peptide apelin lowers blood pressure via a nitric oxidedependent mechanism. Regul Pept 2001;99:87e92. [53] Zhong JC, Yu XY, Huang Y, Yung LM, Lau CW, Lin SG. Apelin modulates aortic vascular tone via endothelial nitric oxide synthase phosphorylation pathway in diabetic mice. Cardiovasc Res 2007;74: 388e95. [54] Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, et al. Adiponectin reduces atherosclerosis in apolipoprotein e-deficient mice. Circulation 2002;106:2767e70.

178

P. Balakumar et al. / Biomedicine & Pharmacotherapy 63 (2009) 171e179

[55] Cheng K, Lam K, Wang Y, Yu H, Carling D, Wu D, et al. Adiponectininduced eNOS activation and nitric oxide production are mediated by APPL1 in endothelial cells. Diabetes 2007;56:1387e94. [56] Takizawa T, Takasaki I, Shionoiri H, Ishii M. Progression of glomerulosclerosis, renal hypertrophy and an increased expression of fibronectin in the renal cortex associated with aging and salt-induced hypertension in Dahl salt-sensitive rats. Life Sci 1997;61:1553e8. [57] Blickle JF, Doucet J, Lrummel T, Hannedouche T. Diabetic nephropathy in the elderly. Diabetes Metab 2007;33:S40e55. [58] Wang Z, Jiang T, Li J, Proctor G, McManaman JM, Lucia S, et al. Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes. Diabetes 2005;54: 2328e35. [59] Wolf G, Ziyadeh FN. Cellular and molecular mechanism of proteinuria in diabetic nephropathy. Nephron Physiol 2007;106:P26e31. [60] Wolf G, Chen S, Ziyadeh FN. From the periphery of the glomerular capillary wall toward the center of disease podocyte injury comes of age in diabetic nephropathy. Diabetes 2005;54:1626e34. [61] Shrinivasan S, Hatley ME, Bolick DT, Palmer LA, Edelstein D, Brownlee M, et al. Hyperglycaemia-induced superoxide production decreases eNOS expression via AP-1 activation in aortic endothelial cells. Diabetologia 2004;47:1727e34. [62] Satchell SC, Tooke JE. What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? Diabetologia 2008;51: 714e25. [63] Kanwar Y, Wada J, Sun L, Xie P, Wallner E, Chen S, et al. Diabetic nephropathy: mechanisms of renal disease progression. Exp Bio Med 2008;233:4e11. [64] Lee EY, Shim MS, Kim MJ, Hong SY, Shin Y, Chung CH. Angiotensin II receptor blocker attenuates overexpression vascular endothelial growth factor in diabetic podocytes. Exp Mol Med 2004;36:65e70. [65] Malyszko J, Malyszko JS, Pawlak K, MysliwiecResistin M. a new adipokine, is related to inflammation and renal function in kidney allograft recipients. Transplant Proc 2006;38:3434e6. [66] Ouchi N, Walsh K. Adiponectin as an anti-inflammatory factor. Clin Chim Acta 2007;380:24e30. [67] Hocher B, Schwarz A, Reinbacher D, Jacobi J, Lun A, Priem F, et al. Effects of endothelin receptor antagonists on the progression of diabetic nephropathy. Nephron 2001;87:161e9. [68] Mallamaci F, Cutrupi S, Pizzini P, Tripepi G, Zoccali C. Urotensin II and biomarkers of endothelial activation and atherosclerosis in endstage renal disease. Am J Hypertens 2006;19:505e10. [69] Sidhart PN, Wagner FD, Bohnemeier H, Jungnik A, Halabi A, Dingemanse S. Pharmacodynamics and pharmacokinetics of the urotensin II receptor antagonist palosuran in macroalbuminuric, diabetic patients. Clin Pharmacol Ther 2006;80:246e56. [70] Matsumoto Y, Ueda S, Yamagishi S, Matsuguma K, Shibata R, Fukami K, et al. Dimethylarginine dimethylaminohydrolase prevents progression of renal dysfunction by inhibiting loss of peritubular capillaries and tubulointerstitial fibrosis in a rat model of chronic kidney disease. J Am Soc Nephrol 2007;18:1365e7. [71] Zager RA, Johnson A, Hanson S, Rosa VD. Altered cholesterol localization and caveolin expression during the evolution of acute renal failure. Kidney Int 2002;61:1674e83. [72] Valles PG, Manucha W, Carrizo L, Vega PJ, Seltzer A, Ruete C. Renal caveolin-1 expression in children with unilateral ureteropelvic junction obstruction. Pediatr Nephrol 2007;22:237e48. [73] Schwedler SB, Guderian F, Dammrich J, Potempa LA, Wanner C. Tubular staining of modified C-reactive protein in diabetic chronic kidney disease. Nephrol Dial Transplant 2003;18:2300e7. [74] Wong CJ, Kim CS, Kim SB, Park SK, Park JS, Lee SK. C-Reactive protein induces NF-kB activation through intracellular calcium and ROS in human mesangial cells. Nephron Exp Nephrol 2005;101:e165e72. [75] Lee MP-S, Orlov D, Sweeney G. Leptin induces rat glomerular mesangial cell hypertrophy, but does not regulate hyperplasia or apoptosis. Int J Obes 2005;29:1395e401. [76] Diez JJ, Jujan J, Iglesias P, Rayes F, Maria J, Abelardo B, et al. Serum concentrations of leptin, adiponectin and resistin, and their relationship

[77]

[78]

[79]

[80]

[81]

[82]

[83] [84] [85]

[86]

[87] [88]

[89] [90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

with cardiovascular disease in patients with end-stage renal disease. Clin Endocrinol 2005;62:242e9. Ellington AA, Malik AR, Klee GG, Turner ST, Rule AD, Mosley TH, et al. Association of plasma resistin with glomerular filtration rate and albuminuria in hypertensive adults. Hypertension 2007;50:708. Eldin W, Ragheb A, Klassen J, Shoker A. Evidence for increased risk of prediabetes in the uremic patient. Nephron Clin Pract 2008;108: c47e55. Ruperez M, Lopez ES, Colio LMB, Esteban V, Vita JR, Plaza JJ, et al. The Rho-kinase pathway regulates angiotensin II-induced renal damage. Kidney Int 2005;68:S39e45. Ishikawa Y, Nishikimi T, Akimoto K, Ishimura K, Ono H, Matsuoka H. Long-term administration of Rho-kinase inhibitor ameliorates renal damage in malignant hypertensive rats. Hypertension 2006;47: 1075e83. Gojo A, Utsunomiya K, Taniguchi K, Yokota T, Ishizawa S, Kanazawa Y, et al. The Rho-kinase inhibitor, fasudil, attenuates diabetic nephropathy in streptozotocin-induced diabetic rats. Eur J Pharmacol 2007;568:242e7. Nishikimi T, Akimoto K, Wang X, Mori Y, Tadokoro K, Ishikawa Y, et al. Fasudil a Rho-kinase inhibitor, attenuates glomerulosclerosis in Dahl salt-sensitive rats. Hypertension 2004;22:1787e96. Kreidberg J. Podocyte differentiation and glomerulogenesis. J Am Soc Nephrol 2003;14:806e14. Lin J, Hu HB, Curhan G. Serum adiponectin and renal dysfunction in men with type 2 diabetes. Diabetes Care 2007;30:239e44. Kobayashi N, Honda T, Yoshida K, Nakano S, Ohno T, Tsubokou Y, et al. Critical role of bradykinin-eNOS and oxidative stress-LOX-1 pathway in cardiovascular remodeling under chronic angiotensin-converting enzyme inhibition. Atherosclerosis 2006;187:92e100. Amann B, Tinzmann R, Angelkort B. ACE inhibitors improve diabetic nephropathy through suppression of renal MCP-1. Diabetes 2003;26: 2421e5. Villa E, Rabano A, Ruilope L, Robles G. Effect of cicaprost and fosinopril on progression of rat diabetic nephropathy. J Hypertens 1997;10:202e8. Blanco S, Vaquero M, Guerrero C, Lopez L, Egido J, Romero R. Potential role of angiotensin-converting enzyme inhibitors and statins on early podocyte damage in a model of type 2 diabetes mellitus, obesity, and mild hypertension. Am J Hypertens 2005;18:557e65. Mimran A, Alfaro V. Candesartan: nephroprotective effects and treatment of diabetic nephropathy. Drugs Today 2003;39:439e50. Singh J, Budhiraja S, Lal H, Arora B. Renoprotection by telmisartan versus benazepril in streptozotocin induced diabetic nephropathy. Iranian J Pharmacol Therap 2006;5:135e9. Sasser JM, Sullivan JC, Hobbs JL, Yamamoto T, Pollock DM, Carmines PK, et al. Endothelin A receptor blockade reduces diabetic renal injury via an anti-inflammatory mechanism. J Am Soc Nephrol 2007;18:143e54. Xu S, Jiang B, Maitland KA, Bayat H, Gu J, Nadler JL, et al. The thromboxane receptor antagonist S18886 attenuates renal oxidant stress and proteinuria in diabetic apolipoprotein e-deficient mice. Diabetes 2006;55:110e9. Chen LL, Zhang JY, Wang BP. Renoprotective effects of fenofibrate in diabetic rats are achieved by suppressing kidney plasminogen activator inhibitor-1. Vascul Pharmacol 2006;44:309e15. Calkin AC, Giunti S, Dahm KJ, Allen TJ, Cooper EM, Thomas MC. PPAR-a and -g agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse. Nephrol Dial Transplant 2006;21: 2399e405. Okada T, Wada J, Hida K, Eguchi J, Hashimoto I, Baba M, et al. Thiazolidinediones ameliorate diabetic nephropathy via cell cycledependent mechanisms. Diabetes 2006;55:1666e77. Usui H, Shikata K, Matsuda M, Okada S, Ogawa D, Yamashita T, et al. HMG-CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats. Nephrol Dial Transplant 2003; 18:265e72. Endres M, Laufs U. Effects of statins on endothelium and signaling mechanisms. Stroke 2004;35:2708e11.

P. Balakumar et al. / Biomedicine & Pharmacotherapy 63 (2009) 171e179 [98] Casey GR, Joyce M, Nagle RG, Chen G, Hayes D. Pravastatin modulates early diabetic nephropathy in an experimental model of diabetic renal disease. J Surg Res 2004;123:176e81. [99] Babaei-Jadidi RB, Karachalias N, Ahmed N, Battah S, Thornalley P. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes 2003;52:2110e20. [100] Sharma S, Anjaneyulu M, Kulkarni S, ChopraResveratrol K. a polyphenolic phytoalexin, attenuates diabetic nephropathy in rats. Pharmacology 2006;76:69e75. [101] Anjaneyulu M, Chopra K. Quercetin, an anti-oxidant bioflavonoid, attenuates diabetic nephropathy in rats. Clin Exp Pharmacol Physiol 2004;31:244e8.

179

[102] Lassila M, Allen TJ, Cao Z, Thallas V, Dahm J, Candido R, et al. Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol 2004;24:935e42. [103] Sato S, Yamate J, Hori Y, Hatai A, Nozawa M, Sagai M. Protective effect of polyphenol-containing azuki bean (Vigna angularis) seed coats on the renal cortex in streptozotocin-induced diabetic rats. J Nutr Biochem 2005;16:547e53. [104] Afshari AT, Shirpoor A, Farshid A, Saadatian R, Rasmi Y, Saboory E, et al. The effect of ginger on diabetic nephropathy, plasma antioxidant capacity and lipid peroxidation in rats. Food Chem 2007;101: 148e53.