Wnt/β-catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction
Wnt/β-catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction
复制标题
Wnt/β-catenin/RAS信号介导年龄相关性肾纤维化并与线粒体功能障碍相关
DOI：
10.1111/acel.13004
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发表时间：
2019-07-18
期刊：
影响因子：
7.8
通讯作者：
Zhou, Lili
中科院分区：
文献类型：
--
作者：
Miao, Jinhua;Liu, Jiafeng;Zhou, Lili
肾纤维化是多种慢性肾脏疾病的共同病理特征。衰老与肾纤维化的进展高度相关。在几个决定因素中，线粒体功能障碍在衰老中起着重要作用。然而，年龄相关性肾纤维化中线粒体功能障碍的潜在机制尚未阐明。在此，我们发现Wnt/β-连环蛋白信号传导和肾素-血管紧张素系统（RAS）活性在衰老肾脏中上调。同时，线粒体的质量和功能随着年龄的增长而受损。Klotho是一种内源性Wnt/β-连环蛋白活性的拮抗剂，其异位表达可消除d-半乳糖（d-gal）诱导的加速衰老小鼠模型中的肾纤维化，并通过保持质量和减少活性氧的产生来显著保护肾线粒体功能。在建立的衰老小鼠模型中，dickkopf 1（一种更特异的Wnt抑制剂）和靶向抗氧化剂mitoquinone恢复了线粒体质量，并减弱了肾小管衰老和肾纤维化。在人近端肾小管细胞系（HKC-8）中，Wnt 1的异位表达降低了生物合成，诱导线粒体功能障碍，并引发细胞衰老。此外，d-gal还能激活Wnt/β-catenin信号通路，进一步激活血管紧张素1型受体（AT 1），导致HKC-8细胞和原代培养肾小管细胞线粒体质量减少，细胞衰老。上述作用可被AT 1阻断剂氯沙坦所抑制。这些结果表明抑制Wnt/β-连环蛋白信号传导和RAS可以减缓年龄相关的线粒体功能障碍和肾纤维化的发生。总之，我们的研究结果表明，Wnt/β-catenin/RAS信号介导年龄相关的肾纤维化，并与线粒体功能障碍。
Renal fibrosis is the common pathological feature in a variety of chronic kidney diseases. Aging is highly associated with the progression of renal fibrosis. Among several determinants, mitochondrial dysfunction plays an important role in aging. However, the underlying mechanisms of mitochondrial dysfunction in age-related renal fibrosis are not elucidated. Herein, we found that Wnt/beta-catenin signaling and renin-angiotensin system (RAS) activity were upregulated in aging kidneys. Concomitantly, mitochondrial mass and functions were impaired with aging. Ectopic expression of Klotho, an antagonist of endogenous Wnt/beta-catenin activity, abolished renal fibrosis in d-galactose (d-gal)-induced accelerated aging mouse model and significantly protected renal mitochondrial functions by preserving mass and diminishing the production of reactive oxygen species. In an established aging mouse model, dickkopf 1, a more specific Wnt inhibitor, and the mitochondria-targeted antioxidant mitoquinone restored mitochondrial mass and attenuated tubular senescence and renal fibrosis. In a human proximal tubular cell line (HKC-8), ectopic expression of Wnt1 decreased biogenesis and induced dysfunction of mitochondria, and triggered cellular senescence. Moreover, d-gal triggered the transduction of Wnt/beta-catenin signaling, which further activated angiotensin type 1 receptor (AT1), and then decreased the mitochondrial mass and increased cellular senescence in HKC-8 cells and primary cultured renal tubular cells. These effects were inhibited by AT1 blocker of losartan. These results suggest inhibition of Wnt/beta-catenin signaling and the RAS could slow the onset of age-related mitochondrial dysfunction and renal fibrosis. Taken together, our results indicate that Wnt/beta-catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction.