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2017 ; 91
(4
): 830-841
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Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal
protection by soluble klotho
#MMPMID27979597
Wu YL
; Xie J
; An SW
; Oliver N
; Barrezueta NX
; Lin MH
; Birnbaumer L
; Huang CL
Kidney Int
2017[Apr]; 91
(4
): 830-841
PMID27979597
show ga
Fibrosis is an exaggerated form of tissue repair that occurs with serious damage
or repetitive injury and ultimately leads to organ failure due to the excessive
scarring. Increased calcium ion entry through the TRPC6 channel has been
associated with the pathogenesis of heart and glomerular diseases, but its role
in renal interstitial fibrosis is unknown. We studied this by deletion of Trpc6
in mice and found it decreased unilateral ureteral obstruction-induced
interstitial fibrosis and blunted increased mRNA expression of fibrosis-related
genes in the ureteral obstructed kidney relative to that in the kidney of
wild-type mice. Administration of BTP2, a pyrazol derivative known to inhibit
function of several TRPC channels, also ameliorated obstruction-induced renal
fibrosis and gene expression in wild-type mice. BTP2 inhibited
carbachol-activated TRPC3 and TRPC6 channel activities in HEK293 cells. Ureteral
obstruction caused over a 10-fold increase in mRNA expression for TRPC3 as well
as TRPC6 in the kidneys of obstructed relative to the sham-operated mice. The
magnitude of protection against obstruction-induced fibrosis in Trpc3 and Trpc6
double knockout mice was not different from that in Trpc6 knockout mice. Klotho,
a membrane and soluble protein predominantly produced in the kidney, is known to
confer protection against renal fibrosis. Administration of soluble klotho
significantly reduced obstruction-induced renal fibrosis in wild-type mice, but
not in Trpc6 knockout mice, indicating that klotho and TRPC6 inhibition act in
the same pathway to protect against obstruction-induced renal fibrosis. Thus
klotho and TRPC6 may be pharmacologic targets for treating renal fibrosis.
|Anilides/*pharmacology
[MESH]
|Animals
[MESH]
|Cytoprotection
[MESH]
|Disease Models, Animal
[MESH]
|Dose-Response Relationship, Drug
[MESH]
|Fibrosis
[MESH]
|Gene Expression Regulation
[MESH]
|Genetic Predisposition to Disease
[MESH]
|Glucuronidase/*pharmacology
[MESH]
|HEK293 Cells
[MESH]
|Humans
[MESH]
|Kidney Diseases/genetics/metabolism/pathology/*prevention & control
[MESH]
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