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This Article Full Text Full Text (PDF) All Versions of this Article: 292/1/F292    most recent 00082.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Shaik, Z. P. Articles by Nowak, G. Search for Related Content PubMed PubMed Citation Articles by Shaik, Z. P. Articles by Nowak, G.

Protein kinase B/Akt modulates nephrotoxicant-induced necrosis in renal cells

Zabeena P. Shaik,^1,2 E. Kim Fifer,¹ and Grayna Nowak¹

¹Department of Pharmaceutical Sciences, College of Pharmacy, and ²Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Submitted 9 March 2006 ; accepted in final form 23 August 2006

Protein kinase B (Akt) activation is well known for its protective effects against apoptosis. However, the role of Akt in regulation of necrosis is unknown. This study was designed to test whether Akt activation protects against nephrotoxicant-induced injury and death in renal proximal tubular cells (RPTC). Exposure of primary cultures of RPTC to the nephrotoxic cysteine conjugate, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), resulted in 9% apoptosis and 30% necrosis at 24 h following the exposure. Akt was activated during 8 h but not at 24 h following toxicant exposure. No RPTC necrosis was observed during Akt activation. Blocking Akt activation using a phosphatidylinositol 3-kinase inhibitor, LY294002 (20 µM), or expressing dominant negative (inactive) Akt increased DCVC-induced RPTC necrosis to 42%. In contrast, Akt activation by expression of constitutively active Akt diminished necrosis to 15%. Modulation of Akt activity had no effect on DCVC-induced apoptosis. DCVC-induced RPTC injury was accompanied by decreases in respiration (51% of controls) and ATP levels (57% of controls). Akt inhibition exacerbated decreases in RPTC respiration and intracellular ATP content (both to 30% of controls). In contrast, Akt activation reduced DCVC-induced decreases in respiration (80% of controls) and prevented decline in ATP content. These data show that in RPTC, Akt activation reduces 1) toxicant-induced mitochondrial dysfunction, 2) decreases in ATP levels, and 3) necrosis. We conclude that Akt activation plays a protective role against necrosis caused by nephrotoxic insult in RPTC. Furthermore, we identified mitochondria as a subcellular target of protective actions of Akt against necrosis.

renal proximal tubular cells; S-(1,2-dichlorovinyl)-L-cysteine; apoptosis; necrosis; ATP; mitochondria

This article has been cited by other articles:

				Z. P. Shaik, E. K. Fifer, and G. Nowak Akt activation improves oxidative phosphorylation in renal proximal tubular cells following nephrotoxicant injury Am J Physiol Renal Physiol, February 1, 2008; 294(2): F423 - F432. [Abstract] [Full Text] [PDF]