[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%, P<0.05), ACC mRNA (40.3%, P<0.05) than those of group OLETF. OLETF/M rats showed lower levels of SREBP-1 (19.3%, P<0.01), FAS mRNA (57.3%, P<0.01), ACC mRNA (22.5%, P<0.05) than those of group OLETF. There was no difference in SREBP-1 mRNA levels for each group.


CONCLUSIONS
Renal damage occurred 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.
Wang
Wei
W
Department of Endocrinology, Peaking University First Hospital, Beijing 100034, China.
Guo
Xiao-hui
XH
Wu
Hong-hua
HH
Wang
Nian-hong
NH
Xu
Xiu-shuang
XS
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000473:pathology; D011345:Fenofibrate / Q000627:therapeutic use*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism; D008687:Metformin / Q000627:therapeutic use*; D051381:Rats; D020334:Rats, Inbred OLETF; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
D051780:Sterol Regulatory Element Binding Protein 1; D008687:Metformin; D011345:Fenofibrate