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

Am J Physiol Renal Physiol. 2008 Feb;294(2):F423-32. doi: 10.1152/ajprenal.00463.2007. Epub 2007 Dec 12.


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 (DeltaPsi(m)); and F(0)F(1)-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 F(0)F(1)-ATPase, and improved DeltaPsi(m). In contrast, inhibiting Akt activation by expressing dominant negative (inactive) Akt or using 20 microM LY294002 exacerbated decreases in electron transport rate, state 3 respiration, ATP production, DeltaPsi(m), and activities of complex I, complex III, and F(0)F(1)-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 DeltaPsi(m), and 3) restoring F(0)F(1)-ATPase activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Animals
  • Cells, Cultured
  • Chromones / pharmacology
  • Cysteine / analogs & derivatives
  • Cysteine / toxicity
  • Electron Transport / drug effects
  • Electron Transport / physiology
  • Electron Transport Complex I / drug effects
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex II / drug effects
  • Electron Transport Complex II / metabolism
  • Electron Transport Complex III / drug effects
  • Electron Transport Complex III / metabolism
  • Electron Transport Complex IV / drug effects
  • Electron Transport Complex IV / metabolism
  • Environmental Pollutants / toxicity
  • Enzyme Inhibitors / pharmacology
  • Kidney Diseases / chemically induced
  • Kidney Diseases / metabolism*
  • Kidney Tubules, Proximal / cytology*
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / physiopathology
  • Membrane Potential, Mitochondrial / drug effects
  • Membrane Potential, Mitochondrial / physiology
  • Mitochondria / drug effects
  • Mitochondria / physiology*
  • Mitochondrial Membranes / metabolism
  • Morpholines / pharmacology
  • Oligomycins / pharmacology
  • Oxidative Phosphorylation / drug effects
  • Oxygen Consumption / drug effects
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / physiology*
  • Proton-Translocating ATPases / antagonists & inhibitors
  • Proton-Translocating ATPases / drug effects
  • Proton-Translocating ATPases / metabolism
  • Rabbits
  • Transfection


  • Chromones
  • Environmental Pollutants
  • Enzyme Inhibitors
  • Morpholines
  • Oligomycins
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • S-(1,2-dichlorovinyl)cysteine
  • Adenosine Triphosphate
  • Electron Transport Complex II
  • Electron Transport Complex IV
  • Proto-Oncogene Proteins c-akt
  • Proton-Translocating ATPases
  • Electron Transport Complex I
  • Electron Transport Complex III
  • Cysteine