Integrin β3 Induction Promotes Tubular Cell Senescence and Kidney Fibrosis.

Shen Li,Qingyan Zhang,Zhihong Liu,Wenju Li,Min Zhao,Chunsun Dai,Chunming Jiang,Daoyuan Lv,Bo Jin,Song Jiang

doi:10.3389/fcell.2021.733831

Abstract

Tubular cell senescence is a common biologic process and contributes to the progression of chronic kidney disease (CKD); however, the molecular mechanisms regulating tubular cell senescence are poorly understood. Here, we report that integrin β3 (ITGB3) expression was increased in tubular cells and positively correlated with fibrosis degree in CKD patients. ITGB3 overexpression could induce p53 pathway activation and the secretion of TGF-β, which, in turn, resulted in senescent and profibrotic phenotype change in cultured tubular cells. Moreover, according to the CMAP database, we identified isoliquiritigenin (ISL) as an agent to inhibit ITGB3. ISL treatment could suppress Itgb3 expression, attenuate cellular senescence, and prevent renal fibrosis in mice. These results reveal a crucial role for integrin signaling in cellular senescence, potentially identifying a new therapeutic direction for kidney fibrosis.

Highlights

Cellular senescence means cells undergoing permanent proliferative arrest with associated changes involving chromatin organization, gene transcription, and protein secretion (Campisi, 2013)
We found that ITGB3 was a hub gene in chronic kidney disease (CKD) patients with tubulointerstitial fibrosis
We found 1,345 differentially expressed genes (DEGs) in GSE30529, 4,024 DEGs in GSE112943, and 5,899 DEGs in GSE99340; only 182 DEGs were shared in diabetic nephropathy (DN), lupus nephritis (LN), and focal segmental glomerulosclerosis (FSGS) patients (Figure 1B and Supplementary Figures 1A–C; for full data, see Supplementary Data 1)

Summary

Introduction

Cellular senescence means cells undergoing permanent proliferative arrest with associated changes involving chromatin organization, gene transcription, and protein secretion (Campisi, 2013). Proximal tubular cell is the major senescent cell type during the chronic injury (Sis et al, 2007). Senescent cells drive kidney fibrosis mainly by producing and releasing senescence-associated secretory phenotype (SASP), a collection of proinflammatory and profibrotic factors and cues, such as interleukin-1β (IL-1β), C-X-C motif chemokine ligand 1 (CXCL1), and transforming growth factor-β1 (TGF-β1). Studies showed that cellular senescence may activate p53, p21, and p16, induce cell cycle arrest, release SASP, and promote renal fibrosis (Yang et al, 2010; Campisi, 2013; Childs et al, 2015). The studies about tubular senescence are mainly focused on the intracellular processes; the extracellular signal delivery of senescence is poorly understood in kidney

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