Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis

Abstract

Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWltch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly upregulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/β-catenin pathway. In mouse tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished TGF-β1-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs cells or normal kidneys increased p16INK4a, p19ARF and p21 expression and senescence-associated β-galactosidase activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by siRNA-mediated p16INK4a silencing in vitro or continuous senolytic treatment with ABT- 263 in vivo. Moreover, BRG1 activated the Wnt/β-catenin pathway, which further inhibited autophagy. Pharmacologic inhibition of the Wnt/β-catenin pathway (ICG-001) or rapamycin-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1-mediated inhibition of autophagy abolished the effects of ICG-001. Further, BRG1 altered the secretome of senescent tubular cells, which promoted proliferation and activation of fibroblasts. Taken together, our results indicate that BRG1 induces tubular senescence by inhibiting autophagy via the Wnt/β-catenin pathway, which ultimately contributes to the development of renal fibrosis.

Cellular senescence: the good, the bad and the unknown

“…Furthermore, uraemic toxins have been implicated in the senescence of proximal tubular cells 193 . Tubular epithelial cell senescence can be induced by inhibition of AMPK–mTOR signalling 194 , activation of the Wnt–β-catenin pathway 195 or overexpression of Wnt9a 196 , and promotes epithelial to mesenchymal transition and consequent fibrosis. α-Klotho, an endogenous antagonist of Wnt–β-catenin signalling, was downregulated in unilateral ureteral obstruction, adriamycin nephropathy, and IRI models of fibrotic kidney disease 197 .…”

Dapagliflozin Alleviates Renal Fibrosis by Inhibiting RIP1-RIP3-MLKL-Mediated Necroinflammation in Unilateral Ureteral Obstruction

“…In our model of UUO, the pathogenesis of renal fibrosis involves a complex network orchestrated by necroptosis, oxidative stress, inflammation, TGF-β1, and activation of Wnt/catenin signaling (Jiang et al, 2015;Dai et al, 2020;Jin et al, 2020). Inhibition of necroptosis or Wnt/catenin signaling alleviates UUO-induced renal fibrosis (Xiao et al, 2017;Gong et al, 2021), implying a relationship between necroptosis and Wnt/ β-catenin signaling. Using in vivo and in vitro studies, we observed that overexpressed Wnt3α/β-catenin/GSK-3β protein in UUO rat kidneys and HK-2 cells was inhibited by either Dapa or ICG-001.…”

JMJD1A/NR4A1 Signaling Regulates the Procession of Renal Tubular Epithelial Interstitial Fibrosis Induced by AGEs in HK-2

“…Renal fibrosis is the main pathological feature in the development stage of DKD (36). Many factors can lead to renal fibrosis in DKD, such as AGEs, mitochondrial dysfunction, autophagy dysfunction, activation of inflammatory pathway and so on (37)(38)(39). AGEs is considered to be an important factor in the process of DKD renal fibrosis, which can promote the process by stimulating the secretion of oxygen free radicals, cytokines, chemokines, adhesion molecules, TGF-β, CTGF, and other mediators (15,40).…”