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

Abstract

The immunosuppressive effect of rapamycin is mediated by inhibition of interleukin-2-stimulated T cell proliferation. We report for the first time that rapamycin also inhibits growth factor-induced proliferation of cultured mouse proximal tubular (MPT; IC(50) ~1 ng/ml) cells and promotes apoptosis of these cells by impairing the survival effects of the same growth factors. On the basis of these in vitro data, we tested the hypothesis that rapamycin would impair recovery of renal function after ischemic acute renal 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-operated animals. In rats subjected to RAO, GFR fell to comparable levels 1 day 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-treated 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 period. Rapamycin also increased apoptosis of tubular cells while markedly reducing their proliferative response after RAO. Furthermore, rapamycin inhibited 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 rapamycin severely impairs the recovery of renal function after ischemia-reperfusion injury. This effect appears to be due to the combined effects of increased tubular cell loss (via apoptosis) and profound inhibition of the regenerative response of tubular cells. These effects are likely mediated by inhibition of p70(S6k).

Sirolimus Prolongs Recovery from Delayed Graft Function After Cadaveric Renal Transplantation

“…The anti-proliferative effect of sirolimus has also been observed in smooth muscle cells, resulting in potent inhibition of neointimal proliferation after balloon-induced vascular injury in animal models (26,27). Interestingly, a recent report strongly suggests that sirolimus may exert a similar anti-proliferative effect in renal tubular cells (28). The authors suggest that 'the combined effects of increased tubular cell loss (via apoptosis) and profound inhibition of the regenerative response of tubular cells' together delayed recovery from ischemia-induced acute renal failure.…”

Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models

“…It is increasingly important to comprehensively understand the role of mTORC1 in acute injury, because adverse clinical effects have been reported associated with sirolimus therapy, especially in the case of lung transplants (25,45,46). In the studies based on animal models, rapamycin treatment has been demonstrated to result in acute renal failure, liver regeneration, and lung injury (39,47,48). In the current study, we demonstrated the positive contribution of mTORC1-mediated S6K1-Stat3 activation in colon tissues toward recovery from acute experimental colitis in mice.…”

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

“…In experimental mesangial proliferative glomerulonephritis and acute renal failure, mTOR inhibitors have been shown to cause inflammation and apoptosis. 60,61 Myocardial infarctions have also been noted. 62 Second, cardiomyocytes have high need for oxygen provided by blood vessels.…”