Transcript MUC1 in the kidney - University of Pittsburgh

The Protective Role of MUC1/β-catenin
Pathway in Acute Kidney Injury​
Mohammad Al-bataineh, DVM, MS, PhD
Post-doctoral Scholar
Rebecca Hughey Laboratory
Renal-Electrolyte Division
N
MUC1 is a transmembrane glycoprotein with an extracellular
mucin-like domain that yields protection from pathogens
O-linked glycans
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
Near perfect
tandem repeats
N-linked glycans
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
Autocatalytic cleavage
within SEA module
membrane
Highly conserved
across species
C
exhibits multiple sites for protein docking and phosphorylation
involved in signal transduction (e.g., HIF1a, GSK3β, β-catenin)
Muc1 is induced during ischemia-reperfusion
injury (IRI)
Muc1 protein - immunblotting
C57BL/6 MICE
19 min ischemia
N=3-5 mice
T= 0-72 h
Muc1 is targeted to the nucleus during IRI (4 h recovery)
Kidney
cortex
Kidney function and morphology are protected
by Muc1 during IRI
C57BL/6 Muc1 KO
t=0
congested
congested
n=3
t=24 h
5, 5, 5, 5
5, 5, 5
n=3-4
t=72 h
recovering
calcification
n=5-6
Wu et al., J. Clin. Invest. 117:2847–2859 (2007)
Muc1 enhances the hypoxia-inducible factor-1
(HIF-1) protective pathway during IRI
19 min ischemia
t=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
Kidney International (2012) 82, 537–547
Kidney function
Kidney morphology
How the b-catenin protective pathway is regulated in
kidneys under metabolic stress conditions like IRI?
In cancer cell lines:
Cancer Res 2005; 65: (22). November 15, 2005
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
SUMMARY
Muc1 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)
Future studies
What is the specific role and mechanism of b-catenin
signaling during kidney injury, recovery and repair?
ACKNOWLEDGMENTS
University of Pittsburgh
Renal-Electrolyte Division
Rebecca Hughey
Carol L Kinlough (Truschel)
Paul Poland
Núria M Pastor-Soler
Funding
NIH R01
NRSA (F32)
NIDDK O’Brien Kidney Center (P30)
Mayo Clinic, Scottsdale, AZ
Department of Pathology
Sandra J Gendler and Cathy S Madsen
Sheldon I Bastacky
Satdarshan (Paul) Monga
Sucha Singh
Indiana University, Indianapolis, IN
Pediatrics
Jackie Ho
Timothy A Sutton and Henry E Mang
Vanderbilt University, Nashville, TN
Volker H Haase and Hanako Kobayashi