Rapamycin attenuates unilateral ureteral obstruction-induced renal fibrosis

Abstract

Unilateral ureteral obstruction (UUO) is a well-characterized hydronephrosis model exhibiting interstitial inflammatory-cell infiltration and tubular dilatation followed by tubulointerstitial fibrosis of the obstructed kidney. Our recent report indicates that rapamycin is effective for 50% of transplant recipients with chronic allograft nephropathy. In this study, we investigate the effect of rapamycin on UUO-induced renal fibrosis. UUO or sham-operated rats were randomly assigned to rapamycin or vehicle and were killed on days 7 and 14 after UUO or sham operation. Rapamycin decreased cross-sectional and gross-morphology changes in the obstructed kidney significantly. Rapamycin markedly blunted the increase in weight of the obstructed kidney, obstructed kidney length, and the obstructed/non-obstructed kidney weight ratio (by 74.6, 42.8, and 61.6% on day 14, respectively, all P<0.01). The scores for tubular dilatation, interstitial volume, interstitial collagen deposition, and alpha-smooth muscle actin (alpha-SMA) after UUO were significantly reduced by rapamycin. Rapamycin also decreased the number of infiltrative anti-ED1-positive cells and the gene expression of transforming growth factor (TGF)-beta1 (84.8 and 80.2% on day 7) after UUO (both P<0.01). By double immunostaining and Western analysis, rapamycin blocked the TGF-beta1-induced loss of E-cadherin expression and de novo increase of the expression of alpha-SMA in a dose-dependent manner. In conclusion, rapamycin significantly attenuated tubulointerstitial damage in a UUO-induced rat model of renal fibrosis, suggesting that rapamycin may have the potential to delay the progression of tubulointerstitial renal fibrosis.

Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis

“…IF coincides with tubular dilation, together referred to as tubulointerstitial injury present in kidneys subjected to UUO (50). Tubular epithelial injury can initiate or sustain progression of fibrosis by different mechanisms such as cytokine production (2,21,51).…”

Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat

“…The beneficial effects of mTOR inhibition have recently been reported in several rat models of chronic kidney disease, i.e., hypertensive 5 ⁄6 nephrectomy, diabetic nephropathy, hypertrophy following unilateral nephrectomy, tubulointerstitial fibrosis due to urethral obstruction or nephrotic syndrome, and polycystic kidney disease (2,5,10,19,26,29). These beneficial results are now expanded toward a progressive model of human mesangioproliferative nephropathy as a leading cause of end-stage kidney disease worldwide (13,14).…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Mycophenolic acid may delay allograft fibrosis by inhibiting TGF-effects (270). Similarly, rapamycine markedly reduced renal fibrosis in the unilateral ureter ligation model associated with an 80% downregulation of intrarenal TGF- (271). Inhibition of the Rho/ROCK pathway, that is a downstream pathway of TGF-, also blocked renal interstitial inflammation and fibrosis (272).…”