title: Mitochondrial Pathology and Glycolytic Shift during Proximal Tubule Atrophy after Ischemic AKI.
abstract: During recovery by regeneration after AKI, proximal tubule cells can fail to redifferentiate, undergo premature growth arrest, and become atrophic. The atrophic tubules display pathologically persistent signaling increases that trigger production of profibrotic peptides, proliferation of interstitial fibroblasts, and fibrosis. We studied proximal tubules after ischemia-reperfusion injury (IRI) to characterize possible mitochondrial pathologies and alterations of critical enzymes that govern energy metabolism. In rat kidneys, tubules undergoing atrophy late after IRI but not normally recovering tubules showed greatly reduced mitochondrial number, with rounded profiles, and large autophagolysosomes. Studies after IRI of kidneys in mice, done in parallel, showed large scale loss of the oxidant-sensitive mitochondrial protein Mpv17L. Renal expression of hypoxia markers also increased after IRI. During early and late reperfusion after IRI, kidneys exhibited increased lactate and pyruvate content and hexokinase activity, which are indicators of glycolysis. Furthermore, normally regenerating tubules as well as tubules undergoing atrophy exhibited increased glycolytic enzyme expression and inhibitory phosphorylation of pyruvate dehydrogenase. TGF-β antagonism prevented these effects. Our data show that the metabolic switch occurred early during regeneration after injury and was reversed during normal tubule recovery but persisted and became progressively more severe in tubule cells that failed to redifferentiate. In conclusion, irreversibility of the metabolic switch, taking place in the context of hypoxia, high TGF-β signaling and depletion of mitochondria characterizes the development of atrophy in proximal tubule cells and may contribute to the renal pathology after AKI.
authors.affiliation: Department of Pathology, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Rongpei
authors.initials: R
authors.lastname: Lan
authors.affiliation: Department of Pathology, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Hui
authors.initials: H
authors.lastname: Geng
authors.affiliation: Department of Pathology, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Prajjal K
authors.initials: PK
authors.lastname: Singha
authors.affiliation: Department of Pathology, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Pothana
authors.initials: P
authors.lastname: Saikumar
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, New York; and.
authors.forename: Erwin P
authors.initials: EP
authors.lastname: Bottinger
authors.affiliation: Department of Medicine, Veterans Affairs Ann Arbor Healthcare System and University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Weinberg
authors.affiliation: Department of Pathology, University of Texas Health Science Center, San Antonio, Texas; venkatachal@uthscsa.edu.
authors.forename: Manjeri A
authors.initials: MA
authors.lastname: Venkatachalam
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications*; D000818:Animals; D001284:Atrophy / Q000209:etiology; D006019:Glycolysis; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000098:blood supply*; D007687:Kidney Tubules, Proximal / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
keywords: ischemia-reperfusion; metabolism; mitochondria; pathology; proximal tubule