Rapamycin delays but does not prevent recovery from acute renal failure: role of acquired tubular resistance.
BACKGROUND
We reported that rapamycin impairs recovery after acute renal failure (ARF) in rats. The objective of this study was to determine if recovery will eventually occur after ARF despite continued rapamycin treatment.


METHODS
ARF was induced in rats by renal artery occlusion. Glomerular filtration rate (GFR), morphology, and tubular cell proliferation were assessed either 2, 4, 6, or 7 days later. Rats were treated daily with rapamycin or vehicle throughout the study. Cultured mouse proximal tubular (MPT) cells were used to compare the antiproliferative effects of rapamycin after exposure for 1 and 7 days.


RESULTS
Two days after ARF, GFR was reduced severely but comparably in vehicle and rapamycin rats. In controls, GFR began to increase after day 2 and was normal by day 6. In rapamycin rats, GFR did begin to improve until after day 4 and reached normal values by day 7. In controls, many proliferating tubular cells were present in outer medulla on day 2, after which proliferation progressively decreased. By contrast, in rapamycin rats, proliferating cells were sparse on day 2, but then increased substantially through days 4 and 6. Cultured MPT cells exposed to rapamycin for 7 days were approximately 10-fold more resistant to the antiproliferative effects of rapamycin than cells exposed for 1 day.


CONCLUSIONS
Rapamycin delays but does not prevent renal recovery after ARF. MPT cells become resistant to rapamycin after prolonged exposure. We speculate that the ultimate recovery of renal function after ARF is due to the development of acquired tubular cell resistance to rapamycin.
Lieberthal
Wilfred
W
Department of Nephrology, Health Science Center, Stony Brook University Hospital, Stony Brook, NY 11794-0001, USA. wlieberthal@notes.cc.sunysb.edu
Fuhro
Robert
R
Andry
Christopher
C
Patel
Vimal
V
Levine
Jerrold S
JS
D058186:Acute Kidney Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004351:Drug Resistance; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage*
D007166:Immunosuppressive Agents; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus