Accelerated Diabetic Nephropathy in Mice Lacking the Peroxisome Proliferator–Activated Receptor α

Park, Cheol Whee; Kim, Hyeong Wook; Ko, Seung Hyun; Chung, Hyun Wha; Lim, Sun Woo; Yang, Chul Woo; Chang, Yoon Sik; Sugawara, Akira; Guan, Youfei; Breyer, Matthew D.

doi:10.2337/diabetes.55.04.06.db05-1329

Cited by 130 publications

(103 citation statements)

References 39 publications

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“…Previously, we found that PPARa activity in kidneys was inversely correlated with lipid accumulation and oxidative stress in type 1 and 2 diabetic animals. 21,22 In this study, we found that oxidative stress, as reflected by glomerular and 24-h urinary 8-OH-dG and 8-epi-PGF 2a levels, was closely related to intrarenal TG and FFA contents. Interestingly, fenofibrate treatment significantly improved reduced systemic and intrarenal bioavailability of NO and completely reversed the oxidative stress and inflammation in kidneys induced by the HF diet.…”

Section: Discussionmentioning

confidence: 80%

“…16 PPARa is also well known as a determinant of the development of hypertension and renal damage, especially in AT-II-induced hypertensive rats. 21,23,24,30 Induction of the renal expression of CYP4A enzymes in the kidney using fibrate compounds has been reported to lower BP in SHR, stroke-prone SHR and Dahl salt-sensitive rats. 31,32 We found the inverse pattern of PPARa expression in kidneys of WKY-HF rats compared with that in SHR-HF animals.…”

Section: Discussionmentioning

confidence: 99%

“…The mesangial matrix and glomerular tuft areas were quantified for each glomerular crosssection as previously reported. 21,22 More than 30 glomeruli, cut through the vascular pole, were counted per kidney, and the average of measured areas was used for analysis. …”

Section: Light Microscope Studymentioning

confidence: 99%

“…20 In kidneys, PPARa expression, often seen in proximal tubules and thick ascending limb, could contribute to a dietary lipid-induced gene expression of peroxisomes and mitochondrial b-oxidation proteins in these segments. 21,22 Fenofibrate, a specific PPARa ligand, participates in the AT-II-dependent BP regulation associated with antagonizing AT-II effects by attenuating angiotensin type 1-mediated but enhancing angiotensin type 2-mediated hemodynamic effects. It does so through NO production, oxidative stress and cytochrome P450-derived eicosanoids in the kidney.…”

Section: Introductionmentioning

confidence: 99%

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Peroxisome proliferator-activated receptor-α activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats

et al. 2009

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We investigated the effects of a high-fat (HF) diet and peroxisome proliferator-activated receptor (PPAR)-a activation on the intrarenal lipotoxicity associated with the renin-angiotensin system (RAS) and oxidative stress using spontaneously hypertensive (SHR) rats. Male SHR and Wistar-Kyoto (WKY) rats at 8 weeks of age were fed either a normal-fat diet or an HF diet without or with fenofibrate treatment for 12 weeks. Severe intrarenal lipid accumulation was noted in the SHR rats fed an HF diet than in WYK rats fed an HF diet (Po0.05). This lipid accumulation was associated with a 70% decrease in renal PPARa expression in SHR rats, whereas an HF diet increased the expression of PPARa in WKY rats by threefold. An HF diet also activated intrarenal, not systemic, RAS and induced oxidative stress associated with reduced nitric oxide (NO) bioavailability. By contrast, fenofibrate attenuated weight gain, fat mass and insulin resistance. Fenofibrate recovered HF diet-induced decreases in intrarenal PPARa expression and fat accumulation, and abolished intrarenal RAS activation and oxidative stress in SHR-HF animals (Po0.01). These activities conferred protection against increased blood pressure (BP), glomerulosclerosis and renal inflammation. Keywords: obesity; oxidative stress; PPARa; renal inflammation; renin-angiotensin system INTRODUCTION Currently, the prevalence of hypertension and chronic renal disease continues to increase among obese individuals. 1,2 It has been suggested that the development and progression of hypertension in an obese patient induces the activation of the systemic renin-angiotensin system (RAS) and the sympathetic nervous system. 3,4 In addition, it increases asymmetric dimethylarginine concentrations and vascular tone created by the reduced bioavailability of nitric oxide (NO) owing to increased oxidative stress. 5,6 Recent reports have demonstrated that it is not the systemic but the local (tissue specific) RAS activation that causes hypertension and renal damage 7-9 associated with local oxidative stress. [10][11][12] It has been shown that oxidative stress in kidneys of diabetic animals, measured by the electron spin resonance imaging technique, 10 high-performance liquid chromatography 13 and immunohistochemistry, 14 can be ameliorated by RAS inhibition.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Light Microscope Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Peroxisome proliferator-activated receptor-α activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats

et al. 2009

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“…However, standardised benchmarks of hyperglycaemia, albuminuria and measurements of renal failure remain to be developed for different inbred strains of mice. The most glaring deficiency has been the lack of a mouse model of diabetes that develops progressively worsening renal insufficiency [63], although recent reports have given positive indications that this experimental problem will be overcome [64,65]. Despite the preceding caveats regarding the difficulties in phenotyping renal function in mice, the use of transgenic mouse models has provided a better understanding of mechanisms that exacerbate diabetic nephropathy [63,66].…”

Section: Retinopathy the Overall Results For Two Studies Of Diabetic Rmentioning

confidence: 99%

Targeting the protein kinase C family in the diabetic kidney: lessons from analysis of mutant mice

2009

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The protein kinase C (PKC) superfamily comprises proteins that are activated in response to various pathogenic stimuli in the diabetic state. Hyperglycaemia is the predominant stimulus that induces the activation of distinct PKC isoforms within a cell, each mediating specific functions, probably through differential subcellular localisation. The contribution of individual PKC isoforms can be directly addressed in vivo using innovative PKC-isoformspecific knockout (KO) mouse models, which are providing key insights into the physiological function of PKC isoform diversity in the development of diabetic nephropathy. Such studies can be a valuable complementary approach to more commonly used pharmacological analyses using agents such as ruboxistaurin mesylate (Arxxant, LY333531), which is claimed to specifically inhibit the PKC-β-isoform. As expected given the multiple and specific properties of the isoforms in vitro, deletion of different PKC isoform signalling pathways leads to distinct phenotypes in mice. Notably, KOs of the individual PKCs assigned specific non-redundant biological functions to each isoform, which were not compensated for by the others. Thus, PKC isoform specificity and cellular diversity seem to be responsible for the divergent outcomes leading to albuminuria and/or renal fibrosis according to studies on the streptozotocin-induced mouse model of diabetes. This review discusses the role of individual PKC isoforms in diabetic nephropathy and their potential therapeutic implications. Defining and targeting mediators of increased intracellular activation in the diabetic microvasculature will have important clinical and therapeutic benefits and help in the design of novel effective therapies in the near future.

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Pathophysiology of the Diabetic Kidney

Vallon

Komers

2011

Comprehensive Physiology

228

178

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Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the molecular mechanism involved and of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. Here we review the pathophysiological changes that occur in the kidney in response to hyperglycemia, including the cellular responses to high glucose and the responses in vascular, glomerular, podocyte, and tubular function. The molecular basis, characteristics, and consequences of the unique growth phenotypes observed in the diabetic kidney, including glomerular structures and tubular segments, are outlined. We delineate mechanisms of early diabetic glomerular hyperfiltration including primary vascular events as well as the primary role of tubular growth, hyperreabsorption, and tubuloglomerular communication as part of a “tubulocentric” concept of early diabetic kidney function. The latter also explains the “salt paradox” of the diabetic kidney, that is, a unique and inverse relationship between glomerular filtration rate and dietary salt intake. The mechanisms and consequences of the intrarenal activation of the renin-angiotensin system and of diabetes-induced tubular glycogen accumulation are discussed. Moreover, we aim to link the changes that occur early in the diabetic kidney including the growth phenotype, oxidative stress, hypoxia, and formation of advanced glycation end products to mechanisms involved in progressive kidney disease.

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Accelerated Diabetic Nephropathy in Mice Lacking the Peroxisome Proliferator–Activated Receptor α

Cited by 130 publications

References 39 publications

Peroxisome proliferator-activated receptor-α activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats

Peroxisome proliferator-activated receptor-α activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats

Targeting the protein kinase C family in the diabetic kidney: lessons from analysis of mutant mice

Pathophysiology of the Diabetic Kidney

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