Glomerular VEGF resistance induced by PKCd/SHP-1 activation and contribution to
diabetic nephropathy.
Authors Mima A, Kitada M, Geraldes P, Li Q, Matsumoto M, Mizutani K, Qi W, Li C, Leitges
M, Rask-Madsen C, King GL
Submitted By Christian Rask-Madsen on 12/10/2012
Status Published
Journal FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Year 2012
Date Published 7/1/2012
Volume : Pages 26 : 2963 - 2974
PubMed Reference 22499584
Abstract This study characterizes the effect of glucose-induced activation of protein
kinase Cd (PKCd) and Src homology-2 domain-containing phosphatase-1 (SHP-1)
expression on vascular endothelial growth factor (VEGF) actions in glomerular
podocytes in cultures and in glomeruli of diabetic rodents. Elevation of glucose
levels induced PKCd and p38 mitogen-activated protein kinase (p38 MAPK) to
increase SHP-1 expression, increased podocyte apoptosis, and inhibited VEGF
activation in podocytes and glomerular endothelial cells. The adverse effects of
high glucose levels can be negated by molecular inhibitors of PKCd, p38MAPK, and
SHP-1 and only partially reduced by antioxidants and nuclear factor-?B (NF-?B)
inhibitor. Increased PKCd activation and SHP-1 expression correlated with loss
of VEGF signaling and podocyte numbers in the glomeruli of diabetic rats and
mice. In contrast, diabetic PKCd-knockout (Prkcd(-/-)) mice did not exhibit
activation of p38 MAPK and SHP-1 or inhibition of VEGF signaling in renal
glomeruli. Functionally, diabetic Prkcd(-/-) mice had decreased expressions of
TGFß, VEGF, and extracellular matrix and less albuminuria than diabetic
Prkcd(+/+) mice. Hyperglycemia and diabetes can cause glomerular podocyte
apoptosis and endothelial dysfunction partly due to increased PKCd/p38 MAPK
activation and the expression of SHP-1 to cause VEGF resistance, independent of
NF-?B activation.


Investigators with authorship
NameInstitution
Christian Rask-MadsenJoslin Diabetes Center - Boston

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