New insights into the role and mechanism of Wnt/β‐catenin signalling in kidney fibrosis

Zuo, Yangyang; Liu, Youhua

doi:10.1111/nep.13472

Cited by 79 publications

(60 citation statements)

References 50 publications

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“…Upon the binding of Wnt ligands to the receptors frizzled (Fzd) and lipoprotein receptor–related protein (LRP) 5/6, GSK3β activity is repressed, and then, β‐catenin would be released and activated to trigger cell injury and renal fibrosis. Although β‐catenin could be up‐regulated in multiple cells such as podocytes, interstitial fibroblasts, endothelial cells and inflammatory cells, it is predominantly localized in renal tubular cells in injured kidneys . These observations suggest the potential relationship between CXCR4 and β‐catenin in renal tubular cell injury and fibrosis.…”

Section: Introductionmentioning

confidence: 94%

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Liu

Feng

Miao

et al. 2020

J Cellular Molecular Medi

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Chronic kidney disease (CKD) has a high prevalence worldwide. Renal fibrosis is the common pathological feature in various types of CKD. However, the underlying mechanisms are not determined. Here, we adopted different CKD mouse models and cultured human proximal tubular cell line to examine the expression of C-X-C motif chemokine receptor 4 (CXCR4) and β-catenin signalling, as well as their relationship in renal fibrosis. In CKD mice and humans with a variety of nephropathies, CXCR4 was dramatically up-regulated in tubules, with a concomitant activation of β-catenin. CXCR4 expression level was positively correlated with the expression of β-catenin target MMP-7. AMD3100, a CXCR4 receptor blocker, and gene knockdown of CXCR4 significantly inhibited the activation of JAK/STAT and β-catenin signalling, protected against tubular injury and renal fibrosis. CXCR4-induced renal fibrosis was inhibited by treatment with ICG-001, an inhibitor of β-catenin signalling. In HKC-8 cells, overexpression of CXCR4 induced activation of β-catenin and deteriorated cell injury. These effects were inhibited by ICG-001. Stromal cell-derived factor (SDF)-1α, the ligand of CXCR4, stimulated the activation of JAK2/STAT3 and JAK3/STAT6 signalling in HKC-8 cells. Overexpression of STAT3 or STAT6 decreased the abundance of GSK3β mRNA. Silencing of STAT3 or STAT6 significantly blocked SDF-1α-induced activation of β-catenin and fibrotic lesions. These results uncover a novel mechanistic linkage between CXCR4 and β-catenin activation in renal fibrosis in association with JAK/STAT/GSK3β pathway. Our studies also suggest that targeted inhibition of CXCR4 may provide better therapeutic effects on renal fibrosis by inhibiting multiple downstream signalling cascades.

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Section: Introductionmentioning

confidence: 94%

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Liu

Feng

Miao

et al. 2020

J Cellular Molecular Medi

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“…Studies by our and others have shown that activation of STAT3 and β‐catenin contributes to renal fibrogenesis 30‐32 . We hypothesized that HDAC8 may also regulate activation of these two signaling pathways.…”

Section: Resultsmentioning

confidence: 93%

Identification of histone deacetylase 8 as a novel therapeutic target for renal fibrosis

et al. 2020

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Histone deacetylases (HDACs) have been shown to alleviate renal fibrosis, however, the role of individual HDAC isoforms in this process is poorly understood. In this study, we examined the role of HDAC8 in the development of renal fibrosis and partial epithelial‐mesenchymal transitions (EMT). In a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO), HDAC8 was primarily expressed in renal tubular epithelial cells and time‐dependently upregulated. This occurred in parallel with the deacetylation of cortactin, a nonhistone substrate of HDAC8, and increased expression of three fibrotic markers: α‐smooth muscle actin, collagen 1, and fibronectin. Administration of PCI34051, a highly selective inhibitor of HDAC8, restored acetylation of contactin and reduced expression of those proteins. PCI34051 treatment also reduced the number of renal tubular epithelial cells arrested at the G2/M phase of the cell cycle and suppressed phosphorylation of Smad3, STAT3, β‐catenin, and expression of Snail after ureteral obstruction. In contrast, HDAC8 inhibition reversed UUO‐induced downregulation of BMP7 and Klotho, two renoprotective proteins. In cultured murine proximal tubular cells, treatment with PCI34051 or specific HDAC8 siRNA was also effective in inhibiting transforming growth factor β1 (TGFβ1)‐induced deacetylation of contactin, EMT, phosphorylation of Smad3, STAT3, and β‐catenin, upregulation of Snail, and downregulation of BMP7 and Klotho. Collectively, these results suggest that HDAC8 activation is required for the EMT and renal fibrogenesis by activation of multiple profibrotic signaling and transcription factors, and suppression of antifibrotic proteins. Therefore, targeting HDAC8 may be novel therapeutic approach for treatment of renal fibrosis.

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“…Of course, targeting only the TGF-β signaling pathway is insu cient to reduce renal brosis. Some studies indicated that CTGF, Wnt/β-catenin, renin-angiotensin system, oxidative stress, and so forth, were implicated in renal brosis [16,30,31]. Wnt/β-catenin is an evolutionarily conserved signaling pathway involved in the regulation of tissue homeostasis, organ development, and injury repair [32].…”

Section: Discussionmentioning

confidence: 99%

“…4c, d, i). Wnt/β-catenin elicited renal brosis by inducing multiple brogenic genes such as RAS components, matrix metalloproteinase-7 (MMP-7), plasminogen activator inhibitor 1 (PAI-1), and Snail1 [31]. Zhou et al described Wnt/β-catenin as the major upstream regulator, which controls the expression of all tested RAS components in the kidneys [38].…”

Section: Discussionmentioning

confidence: 99%

Extract of Corallodiscus Flabellata Attenuates Renal Fibrosis in Aging Mice via the Wnt/β-catenin/RAS Signaling Pathway

Cao

Zeng

et al. 2020

Preprint

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Abstract Background: Renal fibrosis is a common pathological feature of chronic kidney disease (CKD). Aging accelerates renal fibrosis and further aggravates the process of CKD. Corallodiscus flabellata B. L. Burtt (C. flabellata) is a commonly used botanical drug in the Chinese population. However, few studies have reported its physiological effects. This study aimed to explore the effect of C. flabellata extract on renal fibrosis in aging mice and identify potentially active compounds. Methods: Using Senescence-accelerated mouse-prone 8 (SAMP8) mice and β-galactosidase (β-gal)-induced normal rat kidney epithelial cells (NRK-52E cells) as a model, to explore the mechanism of C. flabellata extract on senescence-related renal fibrosis, and initially clarified the material basis of C. flabellata. Results: The C. flabellata extract reduced the senescence and fibrosis of the kidneys in SAMP8 mice by activating nuclear factor erythroid 2–related factor 2 (Nrf2) to balance oxidative stress and inflammation, and interrupting the fibrinogen signaling in the Wnt/β-catenin/renin–angiotensin system. Moreover, 3,4-dihydroxyphenylethanol (SDC-0-14, 16) and (3,4-dihydroxyphenylethanol-8-O-[4-O-trans-caffeoyl-β-D-apiofuranosyl-(1→3)-β-D-glucopyranosyl (1→6)]-β-D-glucopyranoside (SDC-1-8) were isolated compounds from C. flabellata, which reduced the senescence of NRK-52E cells, and maybe the material basis for the function of C. flabellata. Conclusion: Our experiments illuminated that the extract of C. flabellata may improve the aging-related renal fibrosis through the Wnt/β-catenin/RAS pathway, and the material basis of its function may be SDC-0-14, 16 and SDC-1- 8.

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New insights into the role and mechanism of Wnt/β‐catenin signalling in kidney fibrosis

Cited by 79 publications

References 50 publications

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Identification of histone deacetylase 8 as a novel therapeutic target for renal fibrosis

Extract of Corallodiscus Flabellata Attenuates Renal Fibrosis in Aging Mice via the Wnt/β-catenin/RAS Signaling Pathway

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