The Inhibitive Effects Of All-trans Retinoic Acid On The Fibrosis Of Kidney In Diabetic Rats

Objective:To investigate whether all-trans retinoic acid (atRA) can delay renal fibrosis in diabetic rats and explore its mechanism. Methods and Results:Part 1:The effect of atRA on the process of renal fibrosis in diabetic ratsMethods:The models of male Sprague-Dawley(SD) rats with diabetes mellitus was induced in by an intraperitoneal in injection (65mg/kg) of streptozotocin(STZ). Blood glucose levels were measured three days after the injection to ensure a diabetic state(≥16.7mmol/L). The rats were assigned to one of the following groups: 1) normal control group (NC);2) diabetic control group(DM), untreated; 3) diabetic group treated by atRA of 20mg·kg-1 once daily by gavage(DM+atRA). The treatment was lasted for 8 weeks or 12 weeks. Blood glucose (BG), blood urea nitrogen (BUN), serum creatinine (Scr), urine creatinine(Ucr), 24 hours urinary protein were measured;index number of kidney hypertrophy (kidey weight/body weight, KW/BW), creatinine clearance (Ccr) were calculated. The structure and ultrastructrue of the kidney were examined by light and electron microscopy. Results:1. The rats in Group DM and Group DM+atRA ate and drunk too much with much urine and thinness, but not in Group NC. No significant differences of the level of blood glucose were found between Group DM and Group DM+atRA(P>0.05), but were always higher than that in Group NC(P<0.01).2. BUN,Scr,Ccr and the 24 h urinary protein in Group DM+atRA were lower than in Group DM(P<0.01) ,but both higher than in Group NC(P<0.01).3. Index number of kidney hypertrophy (KW/BW) in Group DM+atRA was lower than in Group DM(P<0.01) ,but both higher than in Group NC(P<0.01).4. HE and PASM stainings showed progressive increases in both glomeruli volume and mesangium matrix in Group DM and Group DM+atRA throughout the experiment period,but both in Group DM+atRA were alleviated in comparison with the Group DM.5. Transmission electron microscope showed that renal GBM in Group DM+atRA was thinner than in Group DM, but thicker than in Group NC .PART 2: The mechanism of atRA delaying progression of renal firosis in the diabetic ratsMethods: The models of male Sprague-Dawley(SD) rats with diabetes mellitus were induced by STZ. Rats in three groups (NC,DM,DM+atRA) sacrificed at 8th week and 12th week. The protein exprssion of bone morphogenetic protein-7(BMP-7),transforming growth factor-β1(TGF-β1) and collagen IV,collagen III in kidney tissues were determined by immunohistochemical technique. The mRNA expression of BMP-7 and TGF-β1 in kidney tissues was quantitatively determined through real time reverse transcription polymerase chain reaction (real time RT-PCR).Results:1.The levels of the protein exprssion of BMP-7 in kidney in Group DM+atRA were much higher than in Group DM(P<0.01), but The levels of TGF-β1 and collagen IV,collagen III lower than Group DM (P<0.01).2.The levels of mRNA exprssion of BMP-7 in kidney in Group DM+atRA were higher than in Group DM(P<0.01), but the levels of TGF-β1 lower than in Group DM (P<0.01).3. The levels of protein and mRNA exprssion of BMP-7 were negatively correlated with the levels of TGF-β1 respectively(r=-0.86 and r=-0.86,P<0.01) .The levels of protein expression of BMP-7 were negatively correlated with the levels of and collagen IV,collagen III.( r=-0.75 and r=-0.71, P<0.01)Conclusion:AtRA can ameliorate the progression of renal lesion,inhibit extracellular matrix accumulation and delay renal firosis in rats with diabetes mellitus ,the mechanism of winch may be correlated with up-regulating BMP-7 expression and down-regulating TGF-β1 expression in kidney tissues.