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Transient Receptor Potential Channel 6 Knockout Ameliorates Kidney Fibrosis by Inhibition of Epithelial-Mesenchymal Transition.

ABSTRACT: Kidney fibrosis is generally confirmed to have a significant role in chronic kidney disease, resulting in end-stage kidney failure. Epithelial-mesenchymal transition (EMT) is an important molecular mechanism contributing to fibrosis. Tubular epithelial cells (TEC), the major component of kidney parenchyma, are vulnerable to different types of injuries and are a significant source of myofibroblast by EMT. Furthermore, TRPC6 knockout plays an anti-fibrotic role in ameliorating kidney damage. However, the relationship between TRPC6 and EMT is unknown. In this study, TRPC6^-/- and wild-type (WT) mice were subjected to a unilateral ureteric obstruction (UUO) operation. Primary TEC were treated with TGF-?1. Western blot and immunofluorescence data showed that fibrotic injuries alleviated with the inhibition of EMT in TRPC6^-/- mice compared to WT mice. The activation of AKT-mTOR and ERK1/2 pathways was down-regulated in the TRPC6^-/- mice, while the loss of Na⁺/K⁺-ATPase and APQ1 was partially recovered. We conclude that TRPC6 knockout may ameliorate kidney fibrosis by inhibition of EMT through down-regulating the AKT-mTOR and ERK1/2 pathways. This could contribute to the development of effective therapeutic strategies on chronic kidney diseases.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7843578 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Transient Receptor Potential Channel 6 Knockout Ameliorates Kidney Fibrosis by Inhibition of Epithelial-Mesenchymal Transition.

Zhang Yanhong Y Yin Nina N Sun Anbang A Wu Qifang Q Hu Wenzhu W Hou Xin X Zeng Xixi X Zhu Min M Liao Yanhong Y

Frontiers in cell and developmental biology 20210115

Kidney fibrosis is generally confirmed to have a significant role in chronic kidney disease, resulting in end-stage kidney failure. Epithelial-mesenchymal transition (EMT) is an important molecular mechanism contributing to fibrosis. Tubular epithelial cells (TEC), the major component of kidney parenchyma, are vulnerable to different types of injuries and are a significant source of myofibroblast by EMT. Furthermore, TRPC6 knockout plays an anti-fibrotic role in ameliorating kidney damage. Howev ...[more]

PMID: 33520986

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Project description:ObjectiveRenal fibrosis is the common pathological foundation of many chronic kidney diseases (CKDs). The aim of this study was to investigate whether Hydroxysafflor yellow A (HSYA) can preserve renal function by inhibiting the progression of renal fibrosis and the potential mechanisms.MethodsRenal fibrosis was induced by unilateral ureteral obstruction (UUO) performed on 7-week-old C57BL/6 mice. HSYA (10, 50 and 100 mg/kg) were intragastrically administered. Sham group and model group were administered with the same volume of vehicle. Serum and kidney samples were collected 14 days after the UUO surgery. Serum biochemical indicators were measured by automatic biochemical analyzer. Histological changes were evaluated by HE and Masson staining. In vitro, the anti-fibrotic effect of HSYA was tested on human recombinant transforming growth factor-?1 (TGF-?1) stimulated HK-2 cells. The protein levels of ?-SMA, collagen-I and fibronectin in kidney tissue and HK-2 cells were measured by immunohistochemistry and immunofluorescence. The protein levels of apoptosis-relative and TGF-?1/Smad3 signaling were detected by western blot.ResultsHSYA slowed the development of renal fibrosis both in vivo and in vitro. In UUO rats, renal function index suggested that HSYA treatment decreased the level of serum creatinine (Scr) and blood urea nitrogen (BUN) rose by UUO (P<0.05). HE staining and Masson staining demonstrated that kidney interstitial fibrosis, tubular atrophy, and inflammatory cell infiltration were notably attenuated in the high-dose HSYA group compared with the model group. The expressions of ?-SMA, collagen-I and fibronectin were decreased in the UUO kidney and HK-2 cells of the HSYA-treatment group. Moreover, HSYA reduced the apoptotic rate of HK-2 cells stimulated by TGF-?1. Further study revealed that HSYA regulated the TGF-?1/Smads signaling pathway both in kidney tissue and HK-2 cells.ConclusionsThese results suggested that HSYA had a protective effect against fibrosis in renal cells, at least partly, through inhibiting TGF-?1/smad3-mediated Epithelial-mesenchymal transition signaling pathway.

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Transient Receptor Potential Channel 6 Knockout Ameliorates Kidney Fibrosis by Inhibition of Epithelial-Mesenchymal Transition.

Publications

Transient Receptor Potential Channel 6 Knockout Ameliorates Kidney Fibrosis by Inhibition of Epithelial-Mesenchymal Transition.

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