Regulation of the mitochondrial permeability transition in kidney proximal tubules and its alteration during hypoxia-reoxygenation.
Development of the mitochondrial permeability transition (MPT) can importantly contribute to lethal cell injury from both necrosis and apoptosis, but its role varies considerably with both the type of cell and type of injury, and it can be strongly opposed by the normally abundant endogenous metabolites ADP and Mg(2+). To better characterize the MPT in kidney proximal tubule cells and assess its contribution to injury to them, we have refined and validated approaches to follow the process in whole kidney proximal tubules and studied its regulation in normoxic tubules and after hypoxia-reoxygenation (H/R). Physiological levels of ADP and Mg(2+) greatly decreased sensitivity to the MPT. Inhibition of cyclophilin D by cyclosporine A (CsA) effectively opposed the MPT only in the presence of ADP and/or Mg(2+). Nonesterified fatty acids (NEFA) had a large role in the decreased resistance to the MPT seen after H/R irrespective of the available substrate or the presence of ADP, Mg(2+), or CsA, but removal of NEFA was less effective at restoring normal resistance to the MPT in the presence of electron transport complex I-dependent substrates than with succinate. The data indicate that the NEFA accumulation that occurs during both hypoxia in vitro and ischemic acute kidney injury in vivo is a critical sensitizing factor for the MPT that overcomes the antagonistic effect of endogenous metabolites and cyclophilin D inhibition, particularly in the presence of complex I-dependent substrates, which predominate in vivo.
Feldkamp
Thorsten
T
Nephrology Division, Dept. of Internal Medicine, Univ. of Michigan Medical Center, Ann Arbor, MI 48109-0676, USA.
Park
Jeong Soon
JS
Pasupulati
Ratna
R
Amora
Daniela
D
Roeser
Nancy F
NF
Venkatachalam
M A
MA
Weinberg
Joel M
JM
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D004347:Drug Interactions; D042967:Electron Transport Complex I / Q000378:metabolism; D004734:Energy Metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008274:Magnesium / Q000494:pharmacology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D010100:Oxygen / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D011817:Rabbits
D000081406:Peptidyl-Prolyl Isomerase F; D005230:Fatty Acids, Nonesterified; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D000244:Adenosine Diphosphate; D016572:Cyclosporine; D021983:Cyclophilins; D042967:Electron Transport Complex I; D008274:Magnesium; D010100:Oxygen; D002118:Calcium