The Experimental Investigation On The Effects Of Pioglitazone (a PPARγ Ligand) On Diabetic Nephropathy In Rats

AIM: Peroxisome proliferator-activated receptor Y (PPAR Y ), a novel nuclear receptor, has become an interesting focus in the recent years because of its involvement in several important physiological and patho-physilogical processes in diabetes, including lipid metabolism, glucose homeostasis, inflammation , tumorigenesis and many others. Thiazolidinediones (TZDs) , PPAR Y ligands, are currently used in the treatment of type 2 diabetes mellitus because of their insulin-sensitizing effects and many others which remains unclear. Some latest investigations have demonstrated that PPARY is functionally expressed in kidney, including renal glomerulus and tubule. Clinical studies have also shown their protective effects on the kidneys in the patients with early diabetic nephropathy by reducing albuminuria. But the mechanism remains unknown. METHORDS: (1) The in vivo study: Diabetic rats were induced by injecting streptozotocin into Wistar rats through the tail vein. The rats were divided into three groups as followings,i.e. normal control, diabetes mellitus, and diabetes mellitus treated with pioglitazone. After 10 weeks, 24 hours' urine was collected and the following indices were investigated: body weight; serum glucose concentration, total urinary excretion of glucose for 24 hours and serum insulin level; serum creatinine, urine microalbumin and N-acetyl- beta-D-glucosaminidase(NAG) to assess renal functional injuries; renal morphological changes by routine pathology ; superoxide dismutase, malondialdehyde level, TGF-B1, CRP, NO and NOS levels in the serum; immunostaining of TGF- B1 and the TGF- B1 mRNA levelby RT-PCR in the renal cortex. (2) The in vitro study: The effects of glucose and pioglitazone on CMC proliferation were investigated by MTT method, CMC TGF-B ,mRNA expression by RT-PCR, and TGF-B1 concentration in the culture supernatant by ELISA. RESULTS: (l)In diabetic rats, hyperglycemia and hypoinsulinemia, weight loss, polyuria and hypoproteinemia were found while serum creatinine, urine microalbumin and urine NAG were elevated and creatinine clearance rate decreased in the diabetic rats. The renal pathology showed glomerular hypertrophy and mesangial matrix expansion in diabetes mellitus group. There is no difference in serum glucose, serum triglyceride and protein level between the diabetic group and the diabetic group treated with pioglitazone while the serum creatinine and the NAG were declined by pioglitazone which is believed to have reversive effects on glomerular hypertrophy and extracellular mesangial matrix expansion. The serum SOD level was increased while the MDA level decreased, inhibiting the NO over-production. Furthermore , TGF-3 , level in serum was decreased, inhibiting TGF- P , mRNA expression in renal cortex. (2) In vitro study the results showed that CMC proliferation, TGF-?, mRNA and protein expression were promoted by hyperglycemia. It is by Pioglitazone that the changes as mentioned above could be reversed. CONCLUSIONS: PPAR y ligand, Pioglitazone, has shown beneficial effects on diabetic renal abnormalities demonstrated both by in vivo and in vitro studies. It seems that the beneficial results are independent of its effects on improving glucose metabolism.