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2017 ; 91
(4
): 896-913
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Activated ERK1/2 increases CD44 in glomerular parietal epithelial cells leading
to matrix expansion
#MMPMID27998643
Roeder SS
; Barnes TJ
; Lee JS
; Kato I
; Eng DG
; Kaverina NV
; Sunseri MW
; Daniel C
; Amann K
; Pippin JW
; Shankland SJ
Kidney Int
2017[Apr]; 91
(4
): 896-913
PMID27998643
show ga
The glycoprotein CD44 is barely detected in normal mouse and human glomeruli, but
is increased in glomerular parietal epithelial cells following podocyte injury in
focal segmental glomerulosclerosis (FSGS). To determine the biological role and
regulation of CD44 in these cells, we employed an in vivo and in vitro approach.
Experimental FSGS was induced in CD44 knockout and wild-type mice with a
cytotoxic podocyte antibody. Albuminuria, focal and global glomerulosclerosis
(periodic acid-Schiff stain), and collagen IV staining were lower in CD44
knockout compared with wild-type mice with FSGS. Parietal epithelial cells had
lower migration from Bowman's capsule to the glomerular tuft in CD44 knockout
mice with disease compared with wild type mice. In cultured murine parietal
epithelial cells, overexpressing CD44 with a retroviral vector encoding CD44 was
accompanied by significantly increased collagen IV expression and parietal
epithelial cell migration. Because our results showed de novo co-staining for
activated ERK1/2 (pERK) in parietal epithelial cells in experimental FSGS, and
also in biopsies from patients with FSGS, two in vitro strategies were employed
to prove that pERK regulated CD44 levels. First, mouse parietal epithelial cells
were infected with a retroviral vector for the upstream kinase MEK-DD to increase
pERK, which was accompanied by increased CD44 levels. Second, in
CD44-overexpressing parietal epithelial cells, decreasing pERK with U0126 was
accompanied by reduced CD44. Finally, parietal epithelial cell migration was
higher in cells with increased and reduced in cells with decreased pERK. Thus,
pERK is a regulator of CD44 expression, and increased CD44 expression leads to a
pro-sclerotic and migratory parietal epithelial cell phenotype.
|Albuminuria/enzymology/genetics/prevention & control
[MESH]