TennesseeGlucagon-like peptide-1 (GLP-1) is a gut incretin hormone and is a new clinically available class of agents for improving of insulin resistance in both animals and humans with type 2 diabetes. These studies aimed to determine whether long-term treatment with a long-acting GLP-1 analog, exendin-4, delayed the progression of diabetes. Male db/db mice and db/m mice at 8 wk of age were treated with exendin-4 for 8 wk, whereas the control db/db mice received only vehicle. Urinary albumin excretion was significantly decreased in db/db mice that were treated with 1 nmol/kg exendin-4 compared with those in db/db mice that were treated with 0.5 nmol/kg exendin-4 and control db/db mice (P < 0.005). Intraperitoneal glucose tolerance test was improved in db/db mice that were treated with 1 nmol/kg exendin-4 compared with other groups (P < 0.05). Despite this, fasting blood glucose, glycated hemoglobin, and creatinine concentrations were not significantly different among db/db mice. Renal histology studies further demonstrated that glomerular hypertrophy, mesangial matrix expansion, TGF-␤1 expression, and type IV collagen accumulation and associated glomerular lipid accumulation were significantly decreased in db/db mice that were treated with 1 nmol/kg exendin-4. Furthermore, there were fewer infiltrating inflammatory cells and apoptotic cells in the glomeruli of db/db mice that were treated with 1 nmol/kg exendin-4 compared with those in the other groups accompanied by an increase in the renal immunoreactivity of peroxisome proliferator-activated receptor ␣ and GLP-1 receptor-positive cells and a decrease in 24-h urinary 8-hydroxy-deoxyguanosine levels (P < 0.01, respectively) along with decreases in lipid content. Taken together, exendin-4 treatment seems to ameliorate diabetic nephropathy together with improvement of the metabolic anomalies. These results suggest that exendin-4 could provide a therapeutic role in diabetic nephropathy that results from type 2 diabetes.

Peroxisome proliferator-activated receptor (PPAR)␣, a member of the ligand-activated nuclear receptor superfamily, plays an important role in lipid metabolism and glucose homeostasis and is highly expressed in the kidney. The present studies were aimed at determining the role of PPAR␣ in the pathogenesis of diabetic nephropathy using PPAR␣-knockout mice and cultured murine mesangial cells. Diabetes was induced using a low-dose streptozotocin protocol in 8-week-old male 129 SvJ PPAR␣-knockout and wild-type mice. Diabetic PPAR␣-knockout and wildtype mice developed elevated fasting blood glucose (P < 0.001) and HbA 1c levels (P < 0.001). Renal functional and histopathological changes in diabetic and nondiabetic PPAR␣-knockout and wild-type mice were evaluated after 16 weeks of hyperglycemia. PPAR␣ immunostaining of the cortical tubules of diabetic wild-type mice was elevated by hyperglycemia. In diabetic PPAR␣-knockout mice, renal disease with accompanying albuminuria, glomerular sclerosis, and mesangial area expansion was more severe than in diabetic wild-type mice (P < 0.05) and was accompanied by increased levels of serum free fatty acids and triglycerides (P < 0.01). Furthermore, they exhibited increased renal immunostaining for type IV collagen and osteopontin, which was associated with increased macrophage infiltration and glomerular apoptosis. There were no significant differences in these indexes of renal disease between nondiabetic PPAR␣-knockout and wild-type mice and diabetic PPAR␣ wild-type mice. In vitro studies demonstrated that high glucose levels markedly increased the expression of type IV collagen, transforming growth factor-␤1, and the number of leukocytes adherent to cultured mesangial cells. Adherence of leukocytes was inhibited by the PPAR␣ agonist fenofibrate. Taken together, PPAR␣ deficiency appears to aggravate the severity of diabetic nephropathy through an increase in extracellular matrix formation, inflammation, and circulating free fatty acid and triglyceride concentrations. PPAR␣ agonists may serve as useful therapeutic agents for type 1 diabetic nephropathy. Diabetes 55: [885][886][887][888][889][890][891][892][893] 2006

Our results demonstrated that PPARα agonists or antioxidants are associated with improvement of the circulating FFA and TGs levels and this prevents HFD-induced renal lipotoxicity and hypertension by the activation of PPARα and its downstream signals of both FoxO3a and PGC-1α.

Our study suggests that a high-fat diet induces fatty kidneys, aggravation of blood pressure and renal inflammation in the SHR. Blockade of oxidative stress by tempol or of RAS by candesartan ameliorates the increase in blood pressure and renal inflammation and improves intrarenal lipid accumulation. Therefore, antioxidants or angiotensin receptor blockers can prevent diet-induced hypertension and renal inflammation in hypertensive rats.

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.