Protective effect of sirolimus against renal fibrosis via blockage of mTOR in rat model and its mechanism / 解放军医学杂志

ABSTRACT

Objective To investigate the protective effects of sirolimus on unilateral ureteral obstruction (UUO) induced renal fibrosis by blockage of mTOR and its mechanism. Methods Forty-two female rats were randomized to 3 groups UUO group, sirolimus group (Sir group), and control group. UUO rats underwent unilateral ureteral ligation to reproduce renal fibrosis model. Sir group received sirolimus 2mg/kg wt per day (0.4ml, intragastric administration) from one day before the UUO procedure to the end of study. The control group underwent surgery but without ureteral ligation. Obstructed kidneys were harvested on 7th and 14th day, and histological examination was performed for observing and comparing the degree of renal and renal tubule expansion. The concentrations of sodium, potassium and calcium ion in the urine obtained from the pelvis of the kidneys with ligated ureters were determined. At the same time, the expression of proliferating cell nuclear antigen (PCNA) and apoptosis were observed with immunohistochemical method and TUNEL respectively. MicroRNAs quantities (mir-29c, mir-143, and mir-155) were assayed by quantitative PCR. Results At abovementioned two time-points, swollen kidneys and expanded renal tubules were observed in UUO and Sir groups as compared to control group, however, kidney in Sir group showed significantly less swelling and than that in UUO group (P<0.01). Histological observation found tubular injury, cellular infiltration, and fibrosis were more marked in UUO group as compared to Sir group. Na+, K+ and Ca2+ of retention urine were significantly lower in Sir group than in UUO group (P<0.05). PCNA-positive cell ratio and apoptosis ratio were higher in UUO group than in Sir and control groups (P<0.01). No significant difference in expression of miR-155 or miR-143 was found between 3 groups, however, miR-29c expression in UUO group was down-regulated and significantly lower than that in control or Sir group (P<0.01). Conclusion With obstruction of the ureter, blocking mTOR pathways by sirolimus can attenuate fibrosis in the affected kidney.