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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/F423    most recent 00463.2007v1 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 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 Web of Science (1) 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.

Akt activation improves oxidative phosphorylation in renal proximal tubular cells following nephrotoxicant injury

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

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

Submitted 5 October 2007 ; accepted in final form 4 December 2007

Previously, we showed that protein kinase B (Akt) activation increases intracellular ATP levels and decreases necrosis in renal proximal tubular cells (RPTC) injured by the nephrotoxicant S-(1, 2-dichlorovinyl)-L-cysteine (DCVC) (Shaik ZP, Fifer EK, Nowak G. Am J Physiol Renal Physiol 292: F292–F303, 2007). This study examined the role of Akt in improving mitochondrial function in DCVC-injured RPTC. Our data show a novel observation that phosphorylated (active) Akt is localized in mitochondria of noninjured RPTC, both in mitoplasts and the mitochondrial outer membrane. Mitochondrial levels of active Akt decreased in nephrotoxicant-injured RPTC, and this decrease was associated with mitochondrial dysfunction. DCVC decreased basal, uncoupled, and state 3 respirations; ATP production; activities of complexes I, II, and III; the mitochondrial membrane potential (_m); and F₀F₁-ATPase activity. Expressing constitutively active Akt in DCVC-injured RPTC increased the levels of phosphorylated Akt in mitochondria, reduced the decreases in basal and uncoupled respirations, increased complex I-coupled state 3 respiration and ATP production, enhanced activities of complex I, complex III, and F₀F₁-ATPase, and improved _m. In contrast, inhibiting Akt activation by expressing dominant negative (inactive) Akt or using 20 µM LY294002 exacerbated decreases in electron transport rate, state 3 respiration, ATP production, _m, and activities of complex I, complex III, and F₀F₁-ATPase. In conclusion, our data show that Akt activation promotes mitochondrial respiration and ATP production in toxicant-injured RPTC by 1) improving integrity of the respiratory chain and maintaining activities of complex I and complex III, 2) reducing decreases in _m, and 3) restoring F₀F₁-ATPase activity.

mitochondria; respiratory complexes; ATP; S-(1,2-dichlorovinyl)-L-cysteine; mitochondrial membrane potential

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