Transplantation. 82(1):17-22, JUL 2006
DOI: 10.1097/01.tp.0000225772.22757.5e
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PMID: 16861936
Issn Print: 0041-1337
Publication Date: 2006/07/01
Rapamycin Delays But Does Not Prevent Recovery from Acute Renal Failure: Role of Acquired Tubular Resistance
Wilfred Lieberthal;Robert Fuhro;Christopher Andry;Vimal Patel;Jerrold Levine;
+ Author Information
1 Department of Nephrology, Health Science Center, Stony Brook University Hospital, Stony Brook, NY.2 Department of Nephrology, Boston Medical Center, Boston, MA.3 Department of Pathology, Boston Medical Center, Boston, MA.4 Department of Nephrology, University of Illinois at Chicago, IL.
Abstract
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.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.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 ∼10-fold more resistant to the antiproliferative effects of rapamycin than cells exposed for 1 day.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.
