title: Cyclophilin D and the mitochondrial permeability transition in kidney proximal tubules after hypoxic and ischemic injury.
abstract: Mitochondrial matrix cyclophilin D (CyPD) is known to promote development of the mitochondrial permeability transition (MPT). Kidney proximal tubule cells are especially prone to deleterious effects of mitochondrial damage because of their dependence on oxidative mitochondrial metabolism for ATP production. To clarify the role of CyPD and the MPT in proximal tubule injury during ischemia-reperfusion (I/R) and hypoxia-reoxygenation (H/R), we assessed freshly isolated tubules and in vivo injury in wild-type (WT) and Ppif(-/-) CyPD-null mice. Isolated mouse tubules developed a sustained, nonesterified fatty acid-mediated energetic deficit after H/R in vitro that could be substantially reversed by delipidated albumin and supplemental citric acid cycle substrates but was not modified by the absence of CyPD. Susceptibility of WT and Ppif(-/-) tubules to the MPT was increased by H/R but was less in normoxic and H/R Ppif(-/-) than WT tubules. Correction of the energetic deficit that developed during H/R strongly increased resistance to the MPT. Ppif(-/-) mice were resistant to I/R injury in vivo spanning a wide range of severity. The data clarify involvement of the MPT in oxygen deprivation-induced tubule cell injury by showing that the MPT does not contribute to the initial bioenergetic deficit produced by H/R but the deficit predisposes to subsequent development of the MPT, which contributes pathogenically to kidney I/R injury in vivo.
authors.affiliation: Nephrology Division, Dept. of Internal Medicine, Rm. 1560, MSRB II, University of Michigan Medical Center, Ann Arbor, MI 48109-0676, USA.
authors.forename: Jeong Soon
authors.initials: JS
authors.lastname: Park
authors.forename: Ratna
authors.initials: R
authors.lastname: Pasupulati
authors.forename: Thorsten
authors.initials: T
authors.lastname: Feldkamp
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Roeser
authors.forename: Joel M
authors.initials: JM
authors.lastname: Weinberg
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology / Q000502:physiology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000502:physiology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005838:Genotype; D000860:Hypoxia / Q000473:pathology*; D066298:In Vitro Techniques; D007511:Ischemia / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008027:Light; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D010539:Permeability; D012079:Renal Circulation / Q000502:physiology; D012542:Scattering, Radiation
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D005230:Fatty Acids, Nonesterified; C000631446:PPIF protein, mouse; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D021983:Cyclophilins; D002118:Calcium