Rapamycin impairs recovery from acute renal failure: role of cell-cycle arrest and apoptosis of tubular cells

The immunosuppressive effect of rapamycin is mediated by inhibition of inte rleukin-2-stimulated T cell proliferation. We report for the first time tha t rapamycin also inhibits growth factor-induced proliferation of cultured m ouse proximal tubular (MPT; IC50 similar to1 ng/ml) cells and promotes apop tosis of these cells by impairing the survival effects of the same growth f actors. On the basis of these in vitro data, we tested the hypothesis that rapamycin would impair recovery of renal function after ischemic acute rena l failure induced in vivo by renal artery occlusion (RAO). Rats given daily injections of rapamycin or vehicle were subjected to RAO or sham surgery. Rapamycin had no effect on the glomerular filtration rate (GFR) of sham-ope rated animals. In rats subjected to RAO, GFR fell to comparable levels 1 da y later in vehicle- and rapamycin-treated rats (0.25 +/- 0.08 and 0.12 +/- 0.05 ml.min(-1).300 g(-1), respectively) (P not significant). In vehicle-tr eated rats subjected to RAO, GFR increased to 0.61 0.08 ml.min(-1).300 g(-1 ) on day 3 (P < 0.02 vs. day 1) and then rose further to 0.99 +/- 0.09 ml . min(-1). 300 g(-1) on day 4 (P < 0.02 vs. day 3). By contrast, GFR did not improve in rapamycin-treated rats subjected to RAO over the same time peri od. Rapamycin also increased apoptosis of tubular cells while markedly redu cing their proliferative response after RAO. Furthermore, rapamycin inhibit ed activation of 70-kDa S6 protein kinase (p70(S6k)) in cultured MPT cells as well as in the renal tissue of rats subjected to RAO. We conclude that r apamycin severely impairs the recovery of renal function after ischemia-rep erfusion injury. This effect appears to be due to the combined effects of i ncreased tubular cell loss (via apoptosis) and profound inhibition of the r egenerative response of tubular cells. These effects are likely mediated by inhibition of p70(S6k).