Muc1 is protective during kidney ischemia - Reperfusion injury

Núria M. Pastor-Soler, Timothy A. Sutton, Henry E. Mang, Carol L. Kinlough, Sandra J Gendler, Cathy S. Madsen, Sheldon I. Bastacky, Jacqueline Ho, Mohammad M. Al-Bataineh, Kenneth R. Hallows, Sucha Singh, Satdarshan P. Monga, Hanako Kobayashi, Volker H. Haase, Rebecca P. Hughey

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Ischemia-reperfusion injury (IRI) due to hypotension is a common cause of human acute kidney injury (AKI). Hypoxia-inducible transcription factors (HIFs) orchestrate a protective response in renal endothelial and epithelial cells in AKI models. As human mucin 1 (MUC1) is induced by hypoxia and enhances HIF-1 activity in cultured epithelial cells, we asked whether mouse mucin 1 (Muc1) regulates HIF-1 activity in kidney tissue during IRI. Whereas Muc1 was localized on the apical surface of the thick ascending limb, distal convoluted tubule, and collecting duct in the kidneys of sham-treated mice, Muc1 appeared in the cytoplasm and nucleus of all tubular epithelia during IRI. Muc1 was induced during IRI, and Muc1 transcripts and protein were also present in recovering proximal tubule cells. Kidney damage was worse and recovery was blocked during IRI in Muc1 knockout mice compared with congenic control mice. Muc1 knockout mice had reduced levels of HIF-1α, reduced or aberrant induction of HIF-1 target genes involved in the shift of glucose metabolism to glycolysis, and prolonged activation of AMP-activated protein kinase, indicating metabolic stress. Muc1 clearly plays a significant role in enhancing the HIF protective pathway during ischemic insult and recovery in kidney epithelia, providing a new target for developing therapies to treat AKI. Moreover, our data support a role specifically for HIF-1 in epithelial protection of the kidney during IRI as Muc1 is present only in tubule epithelial cells.

Original languageEnglish (US)
Pages (from-to)F1452-F1462
JournalAmerican Journal of Physiology - Renal Physiology
Volume308
Issue number12
DOIs
StatePublished - Jun 15 2015

Keywords

  • Acute kidney injury
  • AMP-activated protein kinase
  • Hypoxia-inducible factor-1 (HIF-1)
  • Ischemia
  • Muc1

ASJC Scopus subject areas

  • Physiology
  • Urology

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  • Cite this

    Pastor-Soler, N. M., Sutton, T. A., Mang, H. E., Kinlough, C. L., Gendler, S. J., Madsen, C. S., Bastacky, S. I., Ho, J., Al-Bataineh, M. M., Hallows, K. R., Singh, S., Monga, S. P., Kobayashi, H., Haase, V. H., & Hughey, R. P. (2015). Muc1 is protective during kidney ischemia - Reperfusion injury. American Journal of Physiology - Renal Physiology, 308(12), F1452-F1462. https://doi.org/10.1152/ajprenal.00066.2015