Wnt/β-catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction.

Jinhua Miao,Jing Niu,Yahong Liu,Chuanjiang Li,Lili Zhou,Yunfang Zhang,Congwei Luo,Fan Fan Hou,Weiwei Shen,Youhua Liu,Hongyan Li,Jiafeng Liu,Peiliang Yang

doi:10.1111/acel.13004

Jinhua Miao, Jing Niu + Show 11 more

Open Access

https://doi.org/10.1111/acel.13004

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Abstract

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.

Highlights

Chronic kidney disease (CKD) has a rapidly rising worldwide prev‐ alence (Bruck et al, 2016; Ku, Johansen, & McCulloch, 2018; Yan et al, 2018)
Our results suggest that Wnt/β‐catenin/renin–angio‐ tensin system (RAS) signaling plays a crucial role in mediating age‐re‐ lated renal fibrosis and is associated with mitochondrial dysfunction
MitoQ blocked the expression of fibronectin and α‐SMA, two well‐known mark‐ ers of renal fibrosis (Figure 8m,o). These results suggest that the Wnt/β‐catenin/RAS axis plays a central role in age‐related renal fibrosis and is associated with mitochondrial dysfunction

Summary

| INTRODUCTION

Chronic kidney disease (CKD) has a rapidly rising worldwide prev‐ alence (Bruck et al, 2016; Ku, Johansen, & McCulloch, 2018; Yan et al, 2018). MitoQ blocked the expression of fibronectin and α‐SMA, two well‐known mark‐ ers of renal fibrosis (Figure 8m,o) These results suggest that the Wnt/β‐catenin/RAS axis plays a central role in age‐related renal fibrosis and is associated with mitochondrial dysfunction. As summarized in Figure 8p, it is concluded that Wnt/β‐ catenin signaling induces RAS activation, which promotes cellular senescence and age‐related kidney fibrosis in association with mi‐ tochondrial dysfunction that stems from a loss of mitochondrial biogenesis. Klotho substantially inhibited d‐gal‐induced upregulation of fibronectin (Figure 9g,j,k) These results further provide striking evidences that Wnt/β‐catenin signaling plays a key role in age‐related mitochondrial dysfunction and renal fi‐ brotic lesions

| DISCUSSION

Findings

| EXPERIMENTAL PROCEDURES