Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho

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Abstract: 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...

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Autores principales: Wu, Yueh-Lin, Xie, Jian, An, Sung-Wan, Oliver, Noelynn, Barrezueta, Nestor X., Lin, Mei-Hsiang, Birnbaumer, Lutz, Huang, Chou Long
Formato: Artículo
Lenguaje:Inglés
Publicado: Elsevier 2019
Materias:
GENETICA
FIBROSIS
RIÑON
ENFERMEDADES RENALES
URETRA
Acceso en línea:https://repositorio.uca.edu.ar/handle/123456789/8753
Aporte de:
Repositorio Institucional de la Universidad Católica Argentina (UCA) de Universidad Católica Argentina
id I33-R139-123456789-8753
record_format dspace
spelling I33-R139-123456789-87532024-03-26T10:32:24Z Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho Wu, Yueh-Lin Xie, Jian An, Sung-Wan Oliver, Noelynn Barrezueta, Nestor X. Lin, Mei-Hsiang Birnbaumer, Lutz Huang, Chou Long GENETICA FIBROSIS RIÑON ENFERMEDADES RENALES URETRA Abstract: 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. 2019-09-17T17:08:45Z 2019-09-17T17:08:45Z 2017 Artículo Wu Y-L, Xie J, An S-W, et al. Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho [en línea]. Kidney International. 2017;91(4):830-841. doi:10.1016/j.kint.2016.09.039 Disponible en: https://repositorio.uca.edu.ar/handle/123456789/8753 0085-2538 (impreso) 1523-1755 (online) https://repositorio.uca.edu.ar/handle/123456789/8753 10.1016/j.kint.2016.09.039 27979597 eng Acceso Abierto http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Elsevier Kidney International. 2017;91(4):830-841
institution Universidad Católica Argentina
institution_str I-33
repository_str R-139
collection Repositorio Institucional de la Universidad Católica Argentina (UCA)
language Inglés
topic GENETICA
FIBROSIS
RIÑON
ENFERMEDADES RENALES
URETRA
spellingShingle GENETICA
FIBROSIS
RIÑON
ENFERMEDADES RENALES
URETRA
Wu, Yueh-Lin
Xie, Jian
An, Sung-Wan
Oliver, Noelynn
Barrezueta, Nestor X.
Lin, Mei-Hsiang
Birnbaumer, Lutz
Huang, Chou Long
Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho
topic_facet GENETICA
FIBROSIS
RIÑON
ENFERMEDADES RENALES
URETRA
description Abstract: 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.
format Artículo
author Wu, Yueh-Lin
Xie, Jian
An, Sung-Wan
Oliver, Noelynn
Barrezueta, Nestor X.
Lin, Mei-Hsiang
Birnbaumer, Lutz
Huang, Chou Long
author_facet Wu, Yueh-Lin
Xie, Jian
An, Sung-Wan
Oliver, Noelynn
Barrezueta, Nestor X.
Lin, Mei-Hsiang
Birnbaumer, Lutz
Huang, Chou Long
author_sort Wu, Yueh-Lin
title Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho
title_short Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho
title_full Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho
title_fullStr Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho
title_full_unstemmed Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho
title_sort inhibition of trpc6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho
publisher Elsevier
publishDate 2019
url https://repositorio.uca.edu.ar/handle/123456789/8753
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