Mohammad Al-bataineh, DVM, MS, PhD Post-doctoral Scholar Rebecca Hughey Laboratory Renal-Electrolyte...
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Transcript of Mohammad Al-bataineh, DVM, MS, PhD Post-doctoral Scholar Rebecca Hughey Laboratory Renal-Electrolyte...
Mohammad Al-bataineh, DVM, MS, PhDPost-doctoral Scholar
Rebecca Hughey LaboratoryRenal-Electrolyte Division
The Protective Role of MUC1/β-catenin Pathway in Acute Kidney Injury
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Autocatalytic cleavage within SEA module
membrane
Near perfect tandem repeats
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d g
lyca
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O-l
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d g
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MUC1 is a transmembrane glycoprotein with an extracellular mucin-like domain that yields protection from pathogens
MUC1 overexpression in tumors is a bad prognosis for the patient
MUC1 expression in tumor cell lines: Pro-survival and anti-apoptotic activities Modulates transcriptional activities after nuclear targeting
Highly conserved across species
exhibits multiple sites for protein docking and phosphorylation involved in signal transduction (e.g., HIF1a, GSK3β, β-catenin)
MUC1 in the kidney: Apical expression on all polarized epithelia during
development Found in the DCT and CD in adult kidneys Found in the PT during development and after injury
Muc1 protein - immunblotting
Muc1 is induced during ischemia-reperfusion injury (IRI)
C57BL/6 MICE19 min ischemiaN=3-5 miceT= 0-72 h
Kidney cortex
Muc1 is targeted to the nucleus during IRI (4 h recovery)
Kidney function and morphology are protected by Muc1 during IRI
C57BL/6 Muc1 KOt=0 congested congested n=3
t=24 h 5, 5, 5, 5 5, 5, 5 n=3-4
t=72 h recovering calcification n=5-6Wu et al., J. Clin. Invest. 117:2847–2859 (2007)
Muc1 enhances the hypoxia-inducible factor-1 (HIF-1) protective pathway during IRI
19 min ischemiat=4 h
lactate dehydrogenase A, enolase, pyruvate kinase M2, and pyruvate dehydrogenase kinase 1
The HIF-1 protective pathway is enhanced by the nuclear targeting of Muc1 in a mouse kidney model of IRI
How the b-catenin protective pathway is regulated in kidneys under metabolic stress conditions like IRI?
Kidney International (2012) 82, 537–547
Kidney function Kidney morphology
Cancer Res 2005; 65: (22). November 15, 2005
In cancer cell lines:
Hypothesis
Muc1 is protective in a mouse kidney model of IRI also through stabilization and transactivation of the b-catenin protective pathway.
Induction of b-catenin during IRI is absent in Muc1 KO mice
b-catenin co-IP with MUC1 in Human kidney proximal tubule HK-2 cells
Nuclear targeting of b-catenin during IRI is absent in Muc1 KO mice
Does MUC1 modulate b-catenin activities during IRI ?
Activation of TCF4 during IRI is significantly reduced in Muc1 KO mice
Activation of Akt is significantly reduced during IRI in the absence of Muc1
Induction of survivin during IRI is absent in Muc1 KO mice
SUMMARYMuc1 stabilizes b-catenin, enhances its nuclear translocation, and augments expression of its downstream targets in a mouse model of AKI.
Muc1 protects the kidney during IRI through transactivation of the b-catenin protective pathway, as evidenced by:
activation of pro-survival factors like activated Akt, survivin, TCF4, and its target cyclin D1
repression of pro-apoptotic factors; such as p53, and cleaved caspase 3 (consistent with decreased apoptosis)
What is the specific role and mechanism of b-catenin signaling during kidney injury, recovery and repair?
Future studies
University of Pittsburgh
Renal-Electrolyte Division
Rebecca Hughey Carol L Kinlough (Truschel)Paul PolandNúria M Pastor-Soler
Department of Pathology
Sheldon I Bastacky Satdarshan (Paul) MongaSucha Singh
Pediatrics
Jackie Ho
Funding
NIH R01NRSA (F32) NIDDK O’Brien Kidney Center (P30)
Mayo Clinic, Scottsdale, AZ
Sandra J Gendler and Cathy S Madsen
Indiana University, Indianapolis, IN
Timothy A Sutton and Henry E Mang
Vanderbilt University, Nashville, TN
Volker H Haase and Hanako Kobayashi
ACKNOWLEDGMENTS