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

Yueh Lin Wu, Jian Xie, Sung Wan An, Noelynn Oliver, Nestor X. Barrezueta, Mei Hsiang Lin, Lutz Birnbaumer, Chou Long Huang

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
JournalKidney International
DOIs
StateAccepted/In press - Feb 24 2016

Fingerprint

Fibrosis
Kidney
Knockout Mice
Ureteral Obstruction
Messenger RNA
HEK293 Cells
Carbachol
Cicatrix
Heart Diseases
Membrane Proteins
Ions
Calcium
Gene Expression
Wounds and Injuries
Genes

Keywords

  • BTP2
  • Fibrosis
  • Klotho
  • TRPC3
  • TRPC6
  • UUO

ASJC Scopus subject areas

  • Medicine(all)
  • Nephrology

Cite this

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.

In: Kidney International, 24.02.2016.

Research output: Contribution to journalArticle

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. In: Kidney International. 2016.
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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 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.",
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