Effect of fenofibrate and metformin on lipotoxicity in OLETF rat kidney

Objective:To explore the possible molecular mechanism of abnormal renal lipid metabolism in OLETF rats, and the effects of fenofibrate or metformin on renal local lipid metabolism. Methods: OLETF rats were randomly divided into three groups:one treated with fenofibrate, one with metformin and one without treatment. LETO rats were used as age-matched normal controls. The animals were sacrificed and the kidneys were obtained respectively at the age of 17 and 30 weeks. 24-hour urine albumin contents and TG contents in renal cortex were measured. The levels of SREBP-1 protein and mRNA in kidney were measured. FAS mRNA and ACC mRNA expressions were measured with RT-PCR. Results:OLETF rats showed characters of obesity, hyperglycemia, hyperlipidemia. At the end of thirty weeks clinical characters of renal damage appeared in OLETF rats, OLETF rats showed higher levels of 24-hour urine albumin contents than those of LETO rats. 24-hour urine albumin contents were correlated positively with TG contents in kidney. The partial correlation coefficient was 0. 870(P = 0.011) by controlling for body weight, serum lipid, blood glucose and fasting insulin concentration. OLETF rats showed higher levels of SREBP-1 protein (43. 2% , P 0. 01 ) , FAS mRNA ( 126. 0% , P 0. 01 ) , ACC mRNA (72. 3% , P 0.01) than those of group LETO. OLETF/F rats showed lower levels of SREBP-1 (15.7%, P =0.061), FAS mRNA (36.8%, P0.05), ACC mRNA (40.3%, P0.05) than those of group OLETF. OLETF/M rats showed lower levels of SREBP-1 (19. 3% , P 0. 01) , FAS mRNA (57.3% , P0.01) , ACC mRNA (22.5% , P0.05) than those of group OLETF. There was no di- fference in SREBP-1 mRNA levels for each group. Conclusion:Renal damage occured in OLETF rats at the prediabetes stage. 24-hour urine albumin contents were correlated positively with TG contents in kidney. SREBP-1 might aggravate fat deposition in kidney through some enzyme associated with fat synthesis , which was a possible pathogenesis of diabetic nephropathy. Treatment with fenofibrate or metformin ameliorated renal damage in OLETF rats through SREBP-1 and some enzyme regulated by it reduced fat deposit in kidney directly.