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

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.

Extract of Corallodiscus Flabellata Attenuates Renal Fibrosis in Aging Mice via the Wnt/β-catenin/RAS Signaling Pathway

“…In mammals, the Wnt family has at least 19 family members critical for kidney development. In senescent kidneys, at least 15 of these family members are upregulated to varying degrees, including Wnt4 [5]. The results of the present study showed that the expression level of Wnt4 protein in the kidneys of SAMP8 mice was signi cantly higher than that in SAMR1 mice, which was veri ed by both Western blot and immunohistochemical analyses (Fig.…”

“…Studies found that SAMP8 mice had age-related renal brosis [5]. First, the SA-β-gal activity in the kidney was observed to investigate whether C. abellata could improve senescence-related renal brosis.…”

“…Aging is closely related to the progression of renal brosis. Studies have shown that mitochondrial dysfunction and kidney brosis are related to the activation of the Wnt/β-catenin signaling pathway and the renin-angiotensin system (RAS) during aging [5]. Severe CKD needs to be treated by hemodialysis and peritoneal dialysis.…”

The emerging role of cellular senescence in renal diseases

“…45 Increased expression of BCL-W and BCL-XL is involved in senescent cell resistance to apoptosis, and inhibition of BCL-W and BCL-XL causes death of senescent cells. 46 According to a recent study, 47 45 In addition, Wnt/β-catenin signalling is involved in the pathogenesis of cellular senescence (Figure 1).…”

“…Wnt/β-catenin signalling is a conserved signalling pathway in organ development that remains silent in normal adult kidneys. 46 According to a recent study, 47…”