PPAR治疗肾病最新综述

Copy CURRENTOPINION PPARg as a therapeutic target in diabetic al diseases d Youfei Guan ARg) is a ligand-activated nuclear transcription factor s in y a pro elin pat etic e, eve t a INTRODUCTION Ithas been reported th 2 diabetes among adu affecting285million a to 7.7% (439 million a alone, theprevalence o is 9.7%, affecting abou 2008 [2 && ]. Clearly, di diabetic nephropathy public health concern one of the major dia leading cause of end accounting for appro cases [3]. Current inter nephropathy include blood pressure, block system, and restrictio Peroxisome proliferator-activated receptors (PPARs) are members of the ligand-activat mone receptor superfamily that con iologic PPARs, have b human ligands Department of Physiology and Pathophysiology, Peking (Beijing) Univer- sity Diabetes Center, Key Laboratory of Molecular Cardiovascular Sci- : youfeiguan@bjmu.edu.cn 1062-48 REVIEW s [5,6]. After being activated by endogenous or synthetic agonists, PPARs form Curr Opin Nephrol Hypertens 2012, 21:97–105 DOI:10.1097/MNH.0b013e32834de526 21 � 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-nephrolhypertens.com r designated as PPARa, PPARb/d and PPARg, een identified in many species including 38 Xu e-mail ight © Lippincott William ree isotypes of and Pathophysiology, Peking (Beijing) University Health Science Center, eyuan Road, Beijing 100191, China. Tel: +86 10 82801447; al processes [4]. To date, th Correspondence to Youfei Guan, MD, PhD, Department of Physiology ed nuclear hor- trol many phys- ences, Peking (Beijing) University Health Science Center, Beijing, China at theglobalprevalenceof type lts (aged 20–79 years) is 6.4%, dults in2010, andwill increase dults) by 2030 [1 && ]. In China f type 2 diabetes among adults t 92million adults in China in abetic renal complication, or , has become a very serious [3]. Diabetic nephropathy is betic complications and the -stage renal disease (ESRD), ximately 40–50% of all new vention strategies for diabetic control of hyperglycemia and age of the renin–angiotensin n of salt and protein intake. heterodimers with another nuclear receptor called retinoid X receptor alpha (RXRa). PPARs/RXRa het- erodimers bind to a specific DNA sequence, PPAR- response element (PPRE), in the promoter regions of the target genes to modulate gene transcription. In addition to this ligand-dependent transactivation mechanism, PPARs also exert their biological actions via an alternative mechanism termed ‘ligand- dependent transrepression’ (Fig. 1). Among the three PPARmembers, PPARg has been receiving increasing attention as it plays an important role in regulating many important physiological processes including glucose and lipidmetabolism, insulin sensitivity, and inflammatory response [7,8]. Synthetic agonists of PPARg, including the thiazolidinediones (TZDs) diabetic nephropathy, hypertension, kidney injury, PPAR nephropathy and other ren Jichun Yang, Yunfeng Zhou, an Purpose of review Peroxisome proliferator-activated receptor gamma (PP that regulates many important physiological processe homeostasis, cell proliferation, inflammation, immunit summarize and discuss recent findings evaluating the with a focus on diabetic nephropathy. We will also d Recent findings PPARg plays important roles in renal physiology and effects against various kidney diseases including diab nephropathy, chemotherapy-associated kidney damag diseases via both systemic and renal actions. Summary PPARg agonists are effective in delaying and even pr especially diabetic nephropathy. PPARg may represen diseases. Keywords s & Wilkins. Unauthorize cluding glucose and lipid metabolism, energy nd reproduction. The current review aims to tective effects of PPARg against kidney diseases eate the potential underlying mechanisms. hophysiology. Agonists of PPARg exert protective nephropathy, ischemic renal injury, IgA polycystic kidney diseases and age-related kidney nting the progression of many renal diseases, promising target for the treatment of renal d reproduction of this article is prohibited. Copyrigh rosiglitazone and pioglitazone, have been widely used for the treatment of hyperglycemia and insulin resistance in clinical settings [9]. PPARg agonists also exert protective effects against various kidney dis- eases including diabetic nephropathy [3,10,11]. In this review, we highlight the latest experimental and clinical studies evaluating the reno-protective effects of PPARg and discuss the underlying mechanisms. EXPRESSION OF PPARg IN THE KIDNEY PPARg is highly expressed in adipose tissues [12], in which it controls adipogenesis and lipid storage. PPARg is also expressed at low levels in many other tissues, including kidney, liver, heart, pancreatic b cells and vascular cells [13,14]. Within the kidney, PPARg is mainly localized in the medullary collect- ing duct [15], with low expression in many other nephron segments, such as the glomeruli and prox- imal tubules [16], and in renal cells including glomerular mesangial cells [17], podocytes [18], and proximal epithelial cells [18,19]. In addition, PPARg is also evident in renal vasculature [20]. Taken together, PPARg is constitutively expressed in the kidney, suggesting that the kidney is a direct target tissue of PPARg agonists. PPARg AND KIDNEY DISEASES In this section, the renoprotective effects andmech- anisms of PPARg in several kidney diseases will be discussed. Reno-protective effect of PPARg from diabetes During the past decade, TZD PPARg agonists rosi- glitazone and pioglitazone have been widely used in clinical treatments of type 2 diabetes. PPARg acti- vation by TZDs is associated with the attenuation of KEY POINTS � PPARg agonists are effective in improving diabetic nephropathy via multiple mechanisms involving activation of PPARg in the kidney and other tissues. � PPARg agonists are also reno-protective in other kidney diseases including polycystic kidney disease, IgA nephropathy, chemotherapy-associated nephropathy and renal ischemia–reperfusion injury. � Novel PPARg agonists with significantly improved efficacy and safety profiles are urgently needed. tra (a) (c) D P P NFκBAP1 PPARγ ligandsCo-repressors DBDDBD RNA Polymerase II FIGURE RXR-a he domain; recuit co insulin se a ligand activator Hormones, autacoids, neurotransmitters and growth factors 98 RNA 9-cis RA PPARγ ligands TZDs P P A R γ R X R α Co-activators (b) PPRE Gene silencing DB A R γ P P A R γ R X R α t © Lippincott Williams & Wilkins. Unauthorized PPRE Polymerase II DBD DBD 1. Schematic model of PPARg action. (a) Ligand-independent re terodimers bind to PPRE and recruit co-repressor complexes that r PPRE, PPAR-response element. (b) Ligand-dependent transactivatio -activators and disassociate with co-repressors, inducing expressio nsitivity regulation, and lipid metabolism. (c) Ligand-dependent tr -dependent manner by antagonizing the actions of other transcrip protein (AP)1. www.co-nephrolhypertens.com reproduction of this article is prohibited. pression. In the absence of specific ligands, PPARg/ epress the gene transcription. DBD, DNA-binding n. Upon ligand binding, PPARg/RXRa heterodimers n of the target genes involved in adipogenesis, ansrepression. PPARg represses gene transcription in tion factors including nuclear factor (NF)-kB and Volume 21 � Number 1 � January 2012 Gene nscription Gene silencing RNA Polymerase II Copyr ize diabetic nephropathy in patients with type 2 dia- betes and in various type 2 diabetic rodent models [21–25]. In streptozotocin (STZ)-induced type 1 dia- betic r protein Recent compe phism of diab [27,28] diabeti signific Therefo and eve multip explain diabeti Impro and h In the p animal researc effectiv orating [7,29]. these b ing live activat esses b involve olism, glycem also po nervou TZD-m critical diabeti of PPA hyperg diabete Impro PPARg vascula suggest the reg PPARg suppor stimula The mo tain se bound treatme nists fr volume vasopressor effect of PPARg activation, implying that the use of PPARg agonists may cause hyperten- sion. Surprisingly, a large body of studies reveal that g ur rte m tio e ion in nc di i an ati rte n w th ng on se t o loo de yp 4, th l c nu in kid nts res nt e k re rea l eti nc he me cy ro , in r lar di I-in gly yst mi )-a Reno-protective effects of PPARg Yang et al. 1062-482 ight © Lippincott Williams & Wilkins. Unauthor odents, PPARg activation also ameliorates uria independent of glycemic control [26]. ly, human genetic studies have provided lling evidence linking Pro12Ala polymor- in the PPARg gene with the development etic nephropathy in type 2 diabetic patients . Moreover, 3-month treatment of type 2 c patients with rosiglitazone resulted in a ant reduction in albuminuria levels [3]. re, activation of PPARg is capable of delaying n preventing diabetic nephropathy. To date, le mechanisms have been proposed to the reno-protective effect of TZDs against c nephropathy [22], as detailed below. vement of systemic insulin sensitivity yperglycemia ast decade, intensive investigation involving experiments, clinical trials and genomic h have revealed that activation of PPARg is e in improving insulin resistance and ameli- hyperglycemia in type 2 diabetes patients Multiple tissues have been implicated in eneficial metabolic actions of PPARg, includ- r, skeletal muscle and adipose tissue. Upon ion, PPARg governs a series of biological proc- y altering a large number of target genes d in peripheral glucose and fatty acid metab- leading to improved insulin sensitivity and ic control [30 & ]. Recently, two elegant studies int to a critical role of PPARg in the central s system, especially in the hypothalamus, in ediated insulin sensitization [31 && ]. Given the role of hyperglycemia in the development of c nephropathy, the glucose-lowering effect Rg agonists may confer protection against lycemia-induced renal damage in type 2 s patients. vement of blood pressure control is expressed in both endothelial cells and r smooth muscle cells (VSMCs) [32–34], ing PPARg may play an important role in ulation of blood pressure. Mice with global gene deletion are hypotensive [32], which is ted by the observation that PPARg agonists te renin gene expression in the kidney [35]. use and human renin gene promoters con- veral PPRE-like sites, which can be directly and activated by PPARg [36]. In addition, nt of rodents and patients with PPARg ago- equently result in fluid retention and blood expansion [37]. These findings suggest a PPAR press hype with dele of th duct of an enha In ad show hum mut hype vatio sure, endo of a mati repre men of b and in h [38,4 may rena Atte The the rode lin patie in th resto whe rena excr enha ing t cell podo neph cells majo tubu inclu sin I estin the s and (TNF 1 � 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins d reproduction of this article is prohibited. activation by TZDs actually reduces blood e and could prevent the development of nsion in animal models and in patients etabolic syndrome [33,38]. Specific PPARg n in renin-producing juxtaglomerular cells kidney unexpectedly increases renin pro- in mice, which is consistent with the results -vitro study showing that PPARg knockdown es PPRE-driven renin transcription [33,39]. tion, mice lacking PPARg in endothelial cells mpaired arterial vasoconstriction [40]. In s, both the Pro12Ala polymorphism and ons in the PPARg gene are associated with nsion [41,42]. Collectively, PPARg acti- is associated with a reduction in blood pres- hich might be in part due to an increase in elial nitric oxide biosynthesis, inhibition iotensin II signaling pathway and inflam- in vascular cells [33,43]. Since hypertension nts a common contributor to the develop- f diabetic nephropathy and intensive control d pressure significantly reduces proteinuria lays the progression of diabetic nephropathy ertensive patients with type 2 diabetes 45], the hypotensive effect of PPARg agonists erefore be beneficial in ameliorating diabetic omplications. ation of renal insulin resistance sulin receptor is constitutively expressed in ney and in most of the renal cell lines of and humans [46,47], suggesting renal insu- istance might occur in type 2 diabetes s. In fact, insulin receptor levels are decreased idneys of insulin-resistant rats, which can be d in part by rosiglitazone treatment [47], s mice with insulin receptor deficiency in epithelial cells exhibit impaired sodium on and increased blood pressure [48]. Insulin es glucose uptake in podocytes by stimulat- translocation of GLUT1 and GLUT4 to the mbrane [49], whereas insulin resistance in tes is associated with proteinuria in diabetic pathy [49,50 & ]. In cultured proximal tubular sulin regulates the expression of megalin, a endocytic receptor responsible for proximal uptake of glomerular-filtered proteins ng albumin, and partially reverses angioten- duced inhibition of megalin [51,52]. Inter- , salicylate, an effective agent in reversing emic insulin resistance of type 2 diabetic rats ce [53], also prevents tumor necrosis factor -induced insulin resistance in HEK293 cells www.co-nephrolhypertens.com 99 Copyrigh d [54]. Therefore, it is reasonable to speculate that the insulin signaling defect in glomerular cells and proximal tubules may contribute to the develop- ment o sitizing diabeti mia-ind express model and ren glitazon Taken t ing is im PPARg by atte kidney Suppr kidney Increas end pr nephro AGE a accumu of plasm kidney by rosi apopto mesang (NF)-kB proxim throug oxygen leading and ex activati induce sion [6 RAGE and m express [63]. C AGE-in RAGE s Attenu stress Inflamm ated wi [64]. In zone re kines i attenua possibl type 1 a evidenc intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of renal dysfunction in type 1 diabetes [22,66]. Recently, TZDs have been reported to amel- e r bit ati al -1 g io ry 7– eti e d an glit t o l o m the mm c eti or ey ea th ete y o nd e-n en hy ki la est ok er -d po ua in lin ia In on ri c o di h on me ein as Hormones, autacoids, neurotransmitters and growth factors 100 t © Lippincott Williams & Wilkins. Unauthorize f diabetic nephropathy and that insulin-sen- PPARg agonists may be useful in preventing c renal injuries. In addition, hyperinsuline- uced transforming growth factor (TGF)-b ion in the kidney of a type 2 diabetic rat was associated with increased proteinuria al dysfunction, which were reversed by pio- e without affecting glycemic control [55]. ogether, it is clear that normal insulin signal- portant formaintaining renal function, and agonists may exert reno-protective effects nuating insulin signaling defect in diabetic s. ession of AGE–RAGE signaling in the ed circulating levels of advanced-glycation oducts (AGEs) is associated with diabetic pathy in rodents and humans [56,57 & ]. dministration induces extracellular matrix lation and renal toxicity via up-regulation inogen activator inhibitor-1 (PAI-1) in the s of normal rats [58], which can be prevented glitazone [58]. In vitro, AGEs promote the sis of human embryonic kidney cells and ial cells via activation of nuclear factor [59]. AGEs also inhibit Naþ/Kþ ATPase in al tubule epithelial cells [60]. AGEs signal h their receptor, RAGE, mediating reactive species (ROS) production, subsequently to activation of the TGF-b–Smad pathway tracellular matrix accumulation [61]. PPARg on has been shown to attenuate AGE- d ROS generation and decrease RAGE expres- 2]. Telmisartan, which can down-regulate expression, inhibits superoxide generation onocyte chemoattractant protein-1 gene ion inmesangial cells via activation of PPARg ollectively, PPARg agonists may attenuate duced renal dysfunction by blocking AGE– ignaling in diabetic kidneys. ation of inflammation and oxidative atory factors are well known to be associ- th the development of diabetic nephropathy diabetic patients, troglitazone and pioglita- duce the serum levels of inflammatory cyto- ncluding IL-1b and PAI-1 [29]. TZDs also te proteinuria and glomerular hypertrophy y via inhibition of renal TGF-b expression in nd type 2 diabetic rats [26,55,65]. Increasing e has revealed an important role of iorat inhi activ theli ICAM PPAR press mato [29,6 diab dativ foun oxid Rosi men rena glyce toge infla may diab Rest kidn Decr with diab stud Finla singl tin g opat and corre sugg adip furth gene and atten nect signa assoc [81]. adip teinu nitri A whic adip treat prot incre www.co-nephrolhypertens.com reproduction of this article is prohibited. enal injury in type 1 diabetic rats through ion of renal ICAM-1 expression and NF-kB on [67]. In cultured proximal tubular epi- cells, rosiglitazone attenuates AGE-induced expression [68]. These findings suggest that may exert its reno-protective effects via sup- n of systemic and renal production of inflam- cytokines in both type 1 and type 2 diabetes 69]. In addition, renal diseases, including c nephropathy, are associated with renal oxi- stress [70,71]. PPARg activation has been to protect from renal damage induced by ts, aging and ischemia/reperfusion [72,73]. azonewas also found to prevent the develop- f diabetic nephropathy by decreasing the xidative stress with slightly reduced hyper- ia in STZ-induced diabetic rats [74]. Taken r, these findings demonstrate that the anti- atory and antioxidative actions of PPARg ontribute to its reno-protective effects in c kidney. ation of adiponectin signaling in the sed serum adiponectin levels are associated e progression of insulin resistance and type 2 s [75,76]. In a large-scale epidemiological f type 1 diabetic patients from Denmark, , and France, Vionnet et al. [77] found ucleotide polymorphisms in the adiponec- e associated with the risk of diabetic nephr- . In obese patients at high risk for diabetes dney disease, albuminuria had a negative tion with plasma adiponectin levels [78], ing adiponectin may be a reno-protective ine in diabetic conditions [79,80]. This is supported by the finding that adiponectin eficient mice exhibit increased albuminuria docyte foot process effacement, which can be ted by exogenous administration of adipo- [78]. In addition, the impaired adiponectin g in the kidney has been proposed to be ted with excessive renal lipid accumulation STZ-induced diabetic rats, viral-mediated ectin overexpression markedly reduces pro- a with increased nephrin and endothelial xide synthase expression in the kidney [82]. ponectin is a direct target gene of PPARg, regulates the expression and secretion of ectin from adipocytes [83,84]. A 3-month nt of rosiglitazone significantly decreases uria in patients with type 2 diabetes, and ed adiponectin levels are independently Volume 21 � Number 1 � January 2012 Copyr ize associated with reduced proteinuria [10]. Our recent study using db/db mice also showed that adminis- tration of PPARa/g dual agonist tesaglitazar signi- ficantly associa adipon (Adipo express AdipoR protein import and cel larly in nectin and gly Taken benefic are ach restora and ex Cell cy Glome pathop diabeti of cycl preven [90]. Co sion in increas is asso increas Pioglita by dow reversin in Otsu Rosiglit tubular mice [9 one an mesang exert i depend indepe Other It has r amylin of rena apopto and so perfuse consist amylin blood diabeti to inhibit amylin expression and secretion from islets [22,103], thereby indirectly contributing to improved diabetic kidney injury. In addition, PPARg al of te ec as g co rta ss cy cys rde l tu . res al ys l f ini & ]. nti do wa rt s c pro ow s h bit lin ee w ge lita cy e s t p ne ep cu act e g o n imal tubular epithelial cells in IgAN by sup- in ng ind Reno-protective effects of PPARg Yang et al. 1062-482 ight © Lippincott Williams & Wilkins. Unauthor attenuated albuminuria, which was ted with a marked elevation of circulating ectin levels [85]. Adiponectin receptor 1 R1)