Journal of the American Society of Nephrology : JASN
Journal of the American Society of Nephrology : JASN
5 years ago

Wnt9a Promotes Renal Fibrosis by Accelerating Cellular Senescence in Tubular Epithelial Cells.

Fan Fan Hou, Congwei Luo, Hongyan Li, Li Yang, Shan Zhou, Lili Zhou, Yunfang Zhang, Jiafeng Liu, Yahong Liu, Youhua Liu, Zhanmei Zhou
Cellular senescence is associated with renal disease progression, and accelerated tubular cell senescence promotes the pathogenesis of renal fibrosis. However, the underlying mechanism is unknown. We assessed the potential role of Wnt9a in tubular cell senescence and renal fibrosis. Compared with tubular cells of normal subjects, tubular cells of humans with a variety of nephropathies and those of several mouse models of CKD expressed high levels of Wnt9a that colocalized with the senescence-related protein p16INK4AWnt9a expression level correlated with the extent of renal fibrosis, decline of eGFR, and expression of p16INK4AFurthermore, ectopic expression of Wnt9a after ischemia-reperfusion injury (IRI) induced activation ofβ-catenin and exacerbated renal fibrosis. Overexpression of Wnt9a exacerbated tubular senescence, evidenced by increased detection of p16INK4Aexpression and senescence-associatedβ-galactosidase activity. Conversely, shRNA-mediated knockdown of Wnt9a repressed IRI-induced renal fibrosisin vivoand impeded the growth of senescent tubular epithelial cells in culture. Notably, Wnt9a-induced renal fibrosis was inhibited by shRNA-mediated silencing of p16INK4Ain the IRI mouse model. In a human proximal tubular epithelial cell line and primary renal tubular cells, Wnt9a remarkably upregulated levels of senescence-related p16INK4A, p19ARF, p53, and p21 and decreased the phosphorylation of retinoblastoma protein. Wnt9a also induced senescent tubular cells to produce TGF-β1, which promoted proliferation and activation in normal rat kidney fibroblasts. Thus, Wnt9a drives tubular senescence and fibroblast activation. Furthermore, the Wnt9a-TGF-βpathway appears to create a reciprocal activation loop between senescent tubular cells and activated fibroblasts that promotes and accelerates the pathogenesis of renal fibrosis.

Publisher URL: http://doi.org/10.1681/ASN.2017050574

DOI: 10.1681/ASN.2017050574

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