Mitochondrial Pathology and Glycolytic Shift during Proximal Tubule Atrophy after Ischemic AKI.

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  • Additional Information
    • Source:
      Publisher: Wolters Kluwer Health, on behalf of the American Society of Nephrology Country of Publication: United States NLM ID: 9013836 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1533-3450 (Electronic) Linking ISSN: 10466673 NLM ISO Abbreviation: J Am Soc Nephrol Subsets: MEDLINE
    • Publication Information:
      Publication: 2023- : Hagerstown, MD : Wolters Kluwer Health, on behalf of the American Society of Nephrology
      Original Publication: Baltimore, MD : Williams & Wilkins, c1990-
    • Subject Terms:
      Glycolysis*; Acute Kidney Injury/*complications ; Ischemia/*complications ; Kidney/*blood supply ; Kidney Tubules, Proximal/*pathology ; Mitochondria/*metabolism ; Mitochondrial Diseases/*etiology; Animals ; Atrophy/etiology ; Mice ; Mice, Inbred C57BL ; Rats ; Rats, Sprague-Dawley
    • 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.
      (Copyright © 2016 by the American Society of Nephrology.)
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    • Grant Information:
      I01 BX002367 United States BX BLRD VA; R01 DK037139 United States DK NIDDK NIH HHS; R01 DK060043 United States DK NIDDK NIH HHS; R01 DK104128 United States DK NIDDK NIH HHS
    • Contributed Indexing:
      Keywords: ischemia-reperfusion; metabolism; mitochondria; pathology; proximal tubule
    • Publication Date:
      Date Created: 20160323 Date Completed: 20170529 Latest Revision: 20181113
    • Publication Date:
      20221213
    • Accession Number:
      PMC5084876
    • Accession Number:
      10.1681/ASN.2015020177
    • Accession Number:
      27000065