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

Abstract

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 p16 Wnt9a expression level correlated with the extent of renal fibrosis, decline of eGFR, and expression of p16 Furthermore, ectopic expression of Wnt9a after ischemia-reperfusion injury (IRI) induced activation of -catenin and exacerbated renal fibrosis. Overexpression of Wnt9a exacerbated tubular senescence, evidenced by increased detection of p16 expression and senescence-associated -galactosidase activity. Conversely, shRNA-mediated knockdown of Wnt9a repressed IRI-induced renal fibrosis and impeded the growth of senescent tubular epithelial cells in culture. Notably, Wnt9a-induced renal fibrosis was inhibited by shRNA-mediated silencing of p16 in the IRI mouse model. In a human proximal tubular epithelial cell line and primary renal tubular cells, Wnt9a remarkably upregulated levels of senescence-related p16, p19, p53, and p21 and decreased the phosphorylation of retinoblastoma protein. Wnt9a also induced senescent tubular cells to produce TGF-1, which promoted proliferation and activation in normal rat kidney fibroblasts. Thus, Wnt9a drives tubular senescence and fibroblast activation. Furthermore, the Wnt9a-TGF- pathway appears to create a reciprocal activation loop between senescent tubular cells and activated fibroblasts that promotes and accelerates the pathogenesis of renal fibrosis.

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

“…Different from its silent expression in normal adult's kidneys, Wnt/β‐catenin signalling is dramatically up‐regulated in CKD‐affected kidneys. The activation of Wnt/β‐catenin signalling is highly associated with oxidative stress, inflammation and cellular senescence . 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.…”

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

“…In the past several years, numerous hypotheses have been postulated, such as partial epithelial-to-mesenchymal transition (EMT), cell cycle arrest, metabolic alterations and accelerated tubular cell senescence. [3][4][5][6] Despite these distinct possibilities, one common and unifying sequel is the conversion of normal tubular cells to a secretory phenotype, characterized by active production and secretion of a range of profibrotic factors, such as transforming growth factor-β (TGF-β), Wnt and hedgehog ligands. [7][8][9][10] Wnt/β-catenin is an evolutionarily conserved, developmental signalling pathway implicated in regulating an assortment of biological processes, such as cell fate determination, tissue homeostasis, organ development and pathogenesis of human diseases.…”

“…In this context, a key question in the field is how the injured tubules trigger interstitial fibroblast activation. In the past several years, numerous hypotheses have been postulated, such as partial epithelial‐to‐mesenchymal transition (EMT), cell cycle arrest, metabolic alterations and accelerated tubular cell senescence . Despite these distinct possibilities, one common and unifying sequel is the conversion of normal tubular cells to a secretory phenotype, characterized by active production and secretion of a range of profibrotic factors, such as transforming growth factor‐β (TGF‐β), Wnt and hedgehog ligands …”

The emerging role of cellular senescence in renal diseases

“…77 In addition, TGF-β1 may induce premature senescence of mesangial cells and myofibroblast-like phenotype transformation, which may contribute to development of glomerulosclerosis. 77 In addition, TGF-β1 may induce premature senescence of mesangial cells and myofibroblast-like phenotype transformation, which may contribute to development of glomerulosclerosis.…”

“…76 Renal fibrosis may be caused by the accelerated senescence of tubular cells; for example, Wnt9a induced senescent tubular cells to produce TGF-β1, driving proliferation and activation of rat kidney fibroblasts. 77 In addition, TGF-β1 may induce premature senescence of mesangial cells and myofibroblast-like phenotype transformation, which may contribute to development of glomerulosclerosis. 78 At the same time, it was reported that G2/M-arrested proximal tubular cells activated c-jun NH(2)-terminal kinase (JNK) signalling, promoting pro-fibrotic cytokine production.…”