Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Nephrology, Huadu District People's Hospital, Southern Medical University, Guangzhou, China.
Aging Cell. 2019 Oct;18(5):e13004. doi: 10.1111/acel.13004. Epub 2019 Jul 18.
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/β-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/β-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/β-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/β-catenin signaling and the RAS could slow the onset of age-related mitochondrial dysfunction and renal fibrosis. Taken together, our results indicate that Wnt/β-catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction.
肾纤维化是多种慢性肾脏病的共同病理特征。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，与年龄相关的肾纤维化中线粒体功能障碍的潜在机制尚不清楚。在此，我们发现 Wnt/β-catenin 信号和肾素-血管紧张素系统 (RAS) 活性在衰老肾脏中上调。同时，线粒体质量和功能随着衰老而受损。Klotho 的异位表达，内源性 Wnt/β-catenin 活性的拮抗剂，可消除半乳糖 (d-gal) 诱导的加速衰老小鼠模型中的肾纤维化，并通过维持质量和减少活性氧的产生来显著保护肾脏线粒体功能。在已建立的衰老小鼠模型中，Dickkopf 1，一种更特异的 Wnt 抑制剂和线粒体靶向抗氧化剂 mitoquinone，恢复了线粒体质量，并减轻了肾小管衰老和肾纤维化。在人近端肾小管细胞系 (HKC-8) 中，Wnt1 的异位表达减少了线粒体的生物发生并诱导了其功能障碍，并引发了细胞衰老。此外，d-gal 触发了 Wnt/β-catenin 信号的转导，进一步激活了血管紧张素受体 1 (AT1)，然后减少了 HKC-8 细胞和原代培养的肾小管细胞中的线粒体质量并增加了细胞衰老。这些作用被血管紧张素受体阻滞剂 losartan 抑制。这些结果表明，抑制 Wnt/β-catenin 信号和 RAS 可以减缓与年龄相关的线粒体功能障碍和肾纤维化的发生。总之，我们的结果表明，Wnt/β-catenin/RAS 信号转导介导与年龄相关的肾纤维化，并与线粒体功能障碍有关。
