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 p16INK4A Wnt9a expression level correlated with the extent of renal fibrosis, decline of eGFR, and expression of p16INK4A Furthermore, ectopic expression of Wnt9a after ischemia-reperfusion injury (IRI) induced activation of β-catenin and exacerbated renal fibrosis. Overexpression of Wnt9a exacerbated tubular senescence, evidenced by increased detection of p16INK4A expression and senescence-associated β-galactosidase activity. Conversely, shRNA-mediated knockdown of Wnt9a repressed IRI-induced renal fibrosis in vivo and impeded the growth of senescent tubular epithelial cells in culture. Notably, Wnt9a-induced renal fibrosis was inhibited by shRNA-mediated silencing of p16INK4A 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 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-β pathway appears to create a reciprocal activation loop between senescent tubular cells and activated fibroblasts that promotes and accelerates the pathogenesis of renal fibrosis.

• Authors: Congwei Luo, Shan Zhou, Zhanmei Zhou, Yahong Liu, Li Yang, Jiafeng Liu, Yunfang Zhang, Hongyan Li, Youhua Liu, Fan Fan Hou, Lili Zhou
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 29 Issue 4 Pg. 1238-1256 (04 2018) ISSN: 1533-3450 [Electronic] United States
• PMID: 29440280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by the American Society of Nephrology.

Chemical References

• CDKN2A protein, human
• Cdkn2a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p16
• Recombinant Proteins
• Transforming Growth Factor beta
• Tumor Suppressor Proteins
• WNT9A protein, human
• Wnt Proteins
• Wnt9a protein, mouse

Topics

• Animals
• Cell Line
• Cellular Senescence (physiology)
• Cyclin-Dependent Kinase Inhibitor p16 (biosynthesis)
• Disease Models, Animal
• Epithelial Cells (pathology)
• Fibroblasts (drug effects)
• Fibrosis
• Gene Expression Regulation
• Genes, p16
• Humans
• Kidney (blood supply, pathology)
• Kidney Tubules (pathology)
• Male
• Mice
• Mice, Inbred C57BL
• RNA Interference
• Rats
• Recombinant Proteins (biosynthesis, genetics)
• Renal Insufficiency, Chronic (chemically induced, genetics, metabolism, pathology)
• Reperfusion Injury (metabolism, pathology)
• Transforming Growth Factor beta (physiology)
• Tumor Suppressor Proteins (biosynthesis, genetics)
• Wnt Proteins (antagonists & inhibitors, genetics, physiology)
• Wnt Signaling Pathway