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1 Renal Section, Evans Memorial Department of Clinical Research, Department of Medicine, 4 Naval Blood Research Laboratory, and 2 Department of Pathology, Boston University Medical Center, Boston 02118; 3 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; and 5 Section of Nephrology, Biological Sciences Division, University of Chicago, Chicago, Illinois 60637
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; IC50 ~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 g1,
respectively) (P = not significant). In vehicle-treated
rats subjected to RAO, GFR increased to 0.61 ± 0.08 ml · min1 · 300 g1 on
day 3 (P < 0.02 vs. day 1) and
then rose further to 0.99 ± 0.09 ml · min1 · 300 g1 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 (p70S6k) 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 p70S6k.
ischemia; proliferation; 70-kDa S6 protein kinase
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