State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital and.
Department of Nephrology, Huadu District People's Hospital, Southern Medical University, Guangzhou, China; and.
J Am Soc Nephrol. 2018 Apr;29(4):1238-1256. doi: 10.1681/ASN.2017050574. Epub 2018 Feb 12.
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.
细胞衰老与肾脏疾病进展有关，加速管状细胞衰老促进了肾脏纤维化的发病机制。然而，其潜在机制尚不清楚。我们评估了 Wnt9a 在管状细胞衰老和肾脏纤维化中的潜在作用。与正常受试者的管状细胞相比，各种肾病患者的管状细胞和几种 CKD 小鼠模型的管状细胞表达高水平的 Wnt9a，该蛋白与衰老相关蛋白 p16 共定位。Wnt9a 的表达水平与肾脏纤维化的程度、eGFR 的下降以及 p16 的表达呈正相关。此外，缺血再灌注损伤（IRI）后 Wnt9a 的异位表达诱导 -连环蛋白的激活并加剧了肾脏纤维化。Wnt9a 的过表达加剧了管状细胞衰老，表现为 p16 表达和衰老相关的 -半乳糖苷酶活性增加。相反，Wnt9a 的 shRNA 介导的敲低抑制了 IRI 诱导的肾脏纤维化和培养中衰老的管状上皮细胞的生长。值得注意的是，在 IRI 小鼠模型中，Wnt9a 诱导的肾脏纤维化被 p16 的 shRNA 介导的沉默所抑制。在人近端肾小管上皮细胞系和原代肾小管细胞中，Wnt9a 显著上调了衰老相关的 p16、p19、p53 和 p21 的水平，并降低了视网膜母细胞瘤蛋白的磷酸化。Wnt9a 还诱导衰老的管状细胞产生 TGF-1，促进正常大鼠肾成纤维细胞的增殖和激活。因此，Wnt9a 驱动管状细胞衰老和成纤维细胞激活。此外，Wnt9a-TGF-途径似乎在衰老的管状细胞和激活的成纤维细胞之间创建了一个相互激活的循环，促进和加速了肾脏纤维化的发病机制。
