Recently there has been a renewal of interest in mitochondrial dysfunction as a mediator of diverse forms of cell injury as a result of new insights into the mechanism for the mitochondrial permeability transition and recognition of the role of mitochondrial cytochrome c release in apoptosis. ATP production in the proximal tubule, a major site of injury during ischemic and toxic forms of acute renal failure, is especially sensitive to mitochondrial dysfunction because, depending on the segment, glcolysis is absent or minimal in proximal tubule cells in vivo. In studies during the present funding period, we have identified a mitochondrial lesion characterized by inhibition of electron transport in complex I associated with matrix condensation and partial deenergization as a functionally important form of mitochondrial injury during hypoxia/reoxygenation of freshly isolated rabbit proximal tubules that play a pivtal role in overall cellular recovery. The lesion: a) precedes the mitochondrial permeability transition and cytochrome c release; b) depresses energetic function of otherwise viable tubules for sustained periods; and c) is highly amenable to prevention and reversal by specific citric acid cycle metabolites that promote anaerobic pathways of intramitochondrial ATP production and electron transport or, under aerobic conditions, bypass the complex I block. The mitochondrial lesion is expressed both in freshly isolated tubules subjected to hypoxia/reoxygeation, and based on ultrastructural changes and modification by citric acid cycle metabolites, during ischemia/reperfusion in vivo. Our general hypothesis is that this form of mitochondrial dysfunction plays a critical role in the outcome of ischemic insults to the kidney and that its amelioration will beneficially impact on cell and tissue recovery from these insults. To test this hypothesis and further investigate its implications for understanding and treating ischemic acute renal failure we propose studies to: 1) Characterize the energetic deficit as it evolves during extended durations of hypoxia/reoxygenation and the effects of protective substrates to ameliorate it under those conditions. 2) Better define the mechanisms for the mitochondrial inner membrane abnormalities during the insult and their relative contributions to the energetic deficit. 3) Assess expression of the lesion and test efficacy of protective metabolites during ischemia/reperfusion of the kidney in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK034275-20
Application #
6777033
Study Section
General Medicine B Study Section (GMB)
Program Officer
Rys-Sikora, Krystyna E
Project Start
1984-07-01
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2006-08-31
Support Year
20
Fiscal Year
2004
Total Cost
$315,359
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Venkatachalam, Manjeri A; Weinberg, Joel M (2017) Pericytes Preserve Capillary Integrity to Prevent Kidney Hypoxia. J Am Soc Nephrol 28:717-719
Bienholz, Anja; Reis, Jonas; Sanli, Pinar et al. (2017) Citrate shows protective effects on cardiovascular and renal function in ischemia-induced acute kidney injury. BMC Nephrol 18:130
Kallingal, George J S; Weinberg, Joel M; Reis, Isildinha M et al. (2016) Long-term response to renal ischaemia in the human kidney after partial nephrectomy: results from a prospective clinical trial. BJU Int 117:766-74
Weinberg, Joel M; Bienholz, Anja; Venkatachalam, M A (2016) The role of glycine in regulated cell death. Cell Mol Life Sci 73:2285-308
Skouta, Rachid; Dixon, Scott J; Wang, Jianlin et al. (2014) Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc 136:4551-6
Bienholz, Anja; Al-Taweel, Ahmad; Roeser, Nancy F et al. (2014) Substrate modulation of fatty acid effects on energization and respiration of kidney proximal tubules during hypoxia/reoxygenation. PLoS One 9:e94584
Linkermann, Andreas; Skouta, Rachid; Himmerkus, Nina et al. (2014) Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci U S A 111:16836-41
Venkatachalam, Manjeri A; Weinberg, Joel M (2013) New wrinkles in old receptors: core fucosylation is yet another target to inhibit TGF-? signaling. Kidney Int 84:11-4
Linkermann, Andreas; Bräsen, Jan Hinrich; Darding, Maurice et al. (2013) Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury. Proc Natl Acad Sci U S A 110:12024-9
Venkatachalam, Manjeri A; Weinberg, Joel M (2013) The conundrum of protection from AKI by adenosine in rodent clamp ischemia models. Kidney Int 84:16-9

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