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Mitochondria Are the Major Targets in Albumin-Induced Apoptosis in Proximal Tubule Cells

Elif Erkan^*,, Prasad Devarajan and George J. Schwartz^*

^* Department of Pediatrics, University of Rochester, School of Medicine, Rochester, New York; Pittsburgh Children's Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania; and Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio

Address correspondence to: Dr. Elif Erkan, Children's Hospital of Pittsburgh, 3705 Fifth Avenue, 412B, Pittsburgh, PA 15213-2583. Phone: 412-692-5182; Fax: 412-692-7443; E-mail: elif.erkan{at}chp.edu

Received for publication April 27, 2006. Accepted for publication February 1, 2007.

Nephrotic-range proteinuria is considered a poor prognostic factor. A correlation between tubulointerstitial injury and the degree of proteinuria is well established. In an attempt to explain the tubular atrophy that is observed in advanced glomerulonephritides, this study investigated apoptotic mechanisms in cultured human proximal tubule cells (HKC-8) that were exposed to endotoxin-free albumin (5, 10, and 20 mg/ml). Apoptosis was detected by Hoechst 33342; annexin staining; and assays for caspases 3, 8, and 9. The apoptotic effect of albumin was maximal at 10 mg/ml albumin, and necrosis prevailed in cells that were incubated with 20 mg/ml. Increase in caspase-9 and -3 activity was observed starting at 6 and maximally at 16 to 24 h. The proapoptotic Bcl-2 protein Bax was upregulated at 6 h, associated with translocation of cytochrome-c from mitochondria to cytosol and alteration in the mitochondrial membrane potential. Production of reactive oxygen species (ROS) was significant at 6 h but declined at 16 and 24 h. Treatment with ROS scavenger dimethylthiourea or antioxidant N-acetylcysteine did not alleviate caspase-3 production. Pan protein kinase C inhibitor bisindolylmaleimide-1 protected the cells from apoptosis. It is concluded that albumin induces apoptosis in human proximal tubule cells by stimulating mitochondrial apoptotic pathway independent of ROS production.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673