Ischemia-reperfusion injury (IRI) due to hypotension is a common cause of human acute kidney injury (AKI). The hypoxia-inducible transcription factors (HIFs) orchestrate a protective response in renal endothelial and epithelial cells in AKI models. As human MUC1 is induced by hypoxia and enhances HIF-1 activity in cultured epithelial cells, we asked whether Muc1 regulates HIF-1 activity in kidney tissue during IRI. While 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 KO mice when compared to congenic controls. Muc1 KO 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 kinase (AMPK), 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.
- Acute kidney injury
- Copyright © 2015, American Journal of Physiology - Renal Physiology