Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor α

Peroxisome proliferator-activated receptor (PPAR)alpha, 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 we-re aimed at determining the role of PPAR(x in the pathogenesis of diabetic nephropathy using PPAR alpha-knockout mice and cultured murine mesangial cells. Diabetes was induced using a low-dose streptozotocin protocol in 8-week-old male 129 SvJ PPAR alpha-knockout and wild-type mice. Diabetic PPARa-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 alpha-knockout and wild-type mice were evaluated after 16 weeks of hyperglycemia. PPAR alpha immunostaining of the cortical tubules of diabetic wild-type mice was elevated by hyperglycemia. In diabetic PPAR alpha-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 alpha-knockout and wild-type mice and diabetic PPAR alpha wild-type mice. In vitro studies demonstrated that high glucose levels markedly increased the expression of type IV collagen, transforming growth factor-beta 1, and the number of leukocytes adherent to cultured mesangial cells. Adherence of leukocytes was inhibited by the PPARa agonist fenofibrate. Taken together, PPAR alpha 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 alpha agonists may serve as useful therapeutic agents for type 1 diabetic nephropathy.