1. ¹Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
2. ²Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
3. ³Chung-Shan Medical University, Taichung, Taiwan
4. ⁴Department of Pathology, Taichung Veterans General Hospital, Taichung, Taiwan
5. ⁵Department of Research, Taichung Veterans General Hospital, Taichung, Taiwan
6. ⁶Department of Pediatric, National Cheng-Kung University, Tainan, Taiwan
7. ⁷Department of Physiology, National Cheng-Kung University, Tainan, Taiwan

Correspondence: M-J Tang, Department of Physiology, National Cheng Kung University Medical College, 1 University Road, Tainan 70101, Taiwan. E-mail: mjtang1@mail.ncku.edu.tw

Received 7 May 2005; Revised 17 September 2005; Accepted 5 October 2005; Published online 15 February 2006.

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 -smooth muscle actin (-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)-1 (84.8 and 80.2% on day 7) after UUO (both P<0.01). By double immunostaining and Western analysis, rapamycin blocked the TGF-1-induced loss of E-cadherin expression and de novo increase of the expression of -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.