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Articles in PresS, published online ahead of print December 4, 2001
Am J Physiol Renal Physiol, 10.1152/ajprenal.00060.2001
Submitted on February 23, 2001
Accepted on November 7, 2001
1 Department of Medicine, University of Minnesota, Minneapolis, MN, USA
2 Department of Medicine, Indiana University Medical Center, Indianapolis, IN, USA; Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA
* To whom correspondence should be addressed. E-mail: girto001{at}umn.edu.
Clusterin is a heterodimeric secreted glycoprotein upregulated following acute renal injury. In aminoglycoside nephrotoxicity clusterin is induced in the tubular epithelium and increased levels are found in the urine. In this study, we developed an in vitro model of gentamicin-induced cytotoxicity in renal proximal tubule cells and tested whether clusterin protected these cells from injury. LLC-PK1 cells were incubated with varying concentrations of gentamicin in serum-free media and cytotoxicity was quantified by LDH release and confirmed by vital dye exclusion. A dose-dependent increase in cytotoxicity occurred with gentamicin concentrations up to 27 mg/ml. Clusterin decreased cytotoxicity in a dose- and time-dependent manner at 6, 12 and 24 hours while albumin, used as a control protein, had no effect. In contrast to the aminoglycoside model, when cells were injured by depletion of ATP clusterin had only a minimal protective effect. LLC-PK1 cells did not express megalin, a receptor that can mediate the uptake of both clusterin and aminoglycosides into proximal tubule cells. Uptake of gentamicin into LLC-PK1 cells was observed despite the absence of megalin. In conclusion, clusterin specifically protects against gentamicin-induced renal tubular cell injury by a megalin-independent mechanism.
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