Muc1 is protective during kidney ischemia-reperfusion injury.
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.
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
Núria M
NM
Pastor-Soler
Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
Timothy A
TA
Sutton
Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
Henry E
HE
Mang
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
Carol L
CL
Kinlough
Department of Immunology and Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Comprehensive Cancer Center, Mayo Clinic in Arizona, Scottsdale, Arizona;
Sandra J
SJ
Gendler
Department of Immunology and Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Comprehensive Cancer Center, Mayo Clinic in Arizona, Scottsdale, Arizona;
Cathy S
CS
Madsen
Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
Sheldon I
SI
Bastacky
Division of Pediatric Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
Jacqueline
J
Ho
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
Mohammad M
MM
Al-Bataineh
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
Kenneth R
KR
Hallows
Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
Sucha
S
Singh
Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
Satdarshan P
SP
Monga
Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee; Medicine and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee; and.
Hanako
H
Kobayashi
Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee; Medicine and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee; and.
Volker H
VH
Haase
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania hugheyr@pitt.edu.
Rebecca P
RP
Hughey
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018396:Mucin-1 / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C060192:MUC1 protein, human; D018396:Mucin-1; C577056:muc1 protein, mouse
AMP-activated protein kinase; Muc1; acute kidney injury; hypoxia-inducible factor-1 (HIF-1); ischemia