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2015 ; 10
(7
): e0132553
Nephropedia Template TP
gab.com Text
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English Wikipedia
Allelic Variants in Arhgef11 via the Rho-Rock Pathway Are Linked to
Epithelial-Mesenchymal Transition and Contributes to Kidney Injury in the Dahl
Salt-Sensitive Rat
#MMPMID26172442
Jia Z
; Johnson AC
; Wang X
; Guo Z
; Dreisbach AW
; Lewin JR
; Kyle PB
; Garrett MR
PLoS One
2015[]; 10
(7
): e0132553
PMID26172442
show ga
Previously, genetic analyses identified that variants in Arhgef11 may influence
kidney injury in the Dahl salt-sensitive (S) rat, a model of hypertensive chronic
kidney disease. To understand the potential mechanism by which altered expression
and/or protein differences in Arhgef11 could play a role in kidney injury, stably
transduced Arhgef11 knockdown cell lines as well as primary cultures of proximal
tubule cells were studied. Genetic knockdown of Arhgef11 in HEK293 and NRK
resulted in reduced RhoA activity, decreased activation of Rho-ROCK pathway, and
less stress fiber formation versus control, similar to what was observed by
pharmacological inhibition (fasudil). Primary proximal tubule cells (PTC)
cultured from the S exhibited increased expression of Arhgef11, increased RhoA
activity, and up regulation of Rho-ROCK signaling compared to control (small
congenic). The cells were also more prone (versus control) to TGF?-1 induced
epithelial-mesenchymal transition (EMT), a hallmark feature of the development of
renal interstitial fibrosis, and characterized by development of spindle shape
morphology, gene expression changes in EMT markers (Col1a3, Mmp9, Bmp7, and Ocln)
and increased expression of N-Cadherin and Vimentin. S derived PTC demonstrated a
decreased ability to uptake FITC-albumin compared to the small congenic in vitro,
which was confirmed by assessment of albumin re-uptake in vivo by infusion of
FITC-albumin and immunofluorescence imaging. In summary, these studies suggest
that genetic variants in the S form of Arhgef11 via increased expression and/or
protein activity play a role in promoting kidney injury in the S rat through
changes in cell morphology (Rho-Rock and/or EMT) that impact the function of
tubule cells.