Dataset Information

β-catenin-controlled tubular cell-derived exosomes play a key role in fibroblast activation via the OPN-CD44 axis.

ABSTRACT: Tubular injury and peripheral fibroblast activation are the hallmarks of chronic kidney disease (CKD), suggesting intimate communication between the two types of cells. However, the underlying mechanisms remain to be determined. Exosomes play a role in shuttling proteins and other materials to recipient cells. In our study, we found that exosomes were aroused by β-catenin in renal tubular cells. Osteopontin (OPN), especially its N-terminal fragment (N-OPN), was encapsulated in β-catenin-controlled tubular cell-derived exosome cargo, and subsequently passed to fibroblasts. Through binding with CD44, exosomal OPN promoted fibroblast proliferation and activation. Gene deletion of β-catenin in tubular cells (Ksp-β-catenin^-/- ) or gene ablation of CD44 (CD44^-/- ) greatly ameliorated renal fibrosis. Notably, N-OPN was carried by exosome and secreted into the urine of patients with CKD, and negatively correlated with kidney function. The urinary exosomes from patients with CKD greatly accelerated renal fibrosis, which was blocked by CD44 deletion. These results suggest that exosome-mediated activation of the OPN/CD44 axis plays a key role in renal fibrosis, which is controlled by β-catenin.

SUBMITTER: Chen S

PROVIDER: S-EPMC8936047 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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β-catenin-controlled tubular cell-derived exosomes play a key role in fibroblast activation via the OPN-CD44 axis.

Chen Shuangqin S Zhang Meijia M Li Jiemei J Huang Jiewu J Zhou Shan S Hou Xiaotao X Ye Huiyun H Liu Xi X Xiang Shaowei S Shen Weiwei W Miao Jinhua J Hou Fan Fan FF Liu Youhua Y Zhou Lili L

Journal of extracellular vesicles 20220301 3

Tubular injury and peripheral fibroblast activation are the hallmarks of chronic kidney disease (CKD), suggesting intimate communication between the two types of cells. However, the underlying mechanisms remain to be determined. Exosomes play a role in shuttling proteins and other materials to recipient cells. In our study, we found that exosomes were aroused by β-catenin in renal tubular cells. Osteopontin (OPN), especially its N-terminal fragment (N-OPN), was encapsulated in β-catenin-controll ...[more]

PMID: 35312232

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Project description: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 SWItch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly up-regulated 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 renal tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished transforming growth factor-β1 (TGF-β1)-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs or normal kidneys increased p16INK4a, p19ARF, and p21 expression and senescence-associated β-galactosidase (SA-β-gal) activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by small interfering RNA (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 (RAPA)-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1 (Baf 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.

Dataset Information

β-catenin-controlled tubular cell-derived exosomes play a key role in fibroblast activation via the OPN-CD44 axis.

Publications

β-catenin-controlled tubular cell-derived exosomes play a key role in fibroblast activation via the OPN-CD44 axis.

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