The CXCR4-AT1 Axis Plays a Vital Role in Glomerular Injury via Mediating the Crosstalk between Podocyte and Mesangial Cell

Wu, Qinyu; Zhou, Shunhua; Xu, Dianguo; Meng, Ping; Chen, Qiurong; Wang, Xiaoxu; Li, Xiaolong; Chen, Shuangqin; Ye, Huiyun; Ye, Wenting; Xiong, Yabing; Li, Jiemei; Jiang, Miao; Sui, Weiwei; Hou, Fan Fan; Liu, Youhua; Zhang, Yunfang; Tang, Ying; Zhou, Lili

doi:10.2139/ssrn.4321512

Cited by 1 publication

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“…[14][15][16] Reports have shown that CXCR4 is significantly upregulated after kidney injury, and the sustaining activation of it aggravates the fibrotic responses. [17][18][19][20] Our previous studies also found that CXCR4 promotes tubular cell injury and renal fibrosis via activating β-catenin signalling. [21][22][23] Wnt/β-catenin signalling is an evolutionarily conserved pathway.…”

Section: Introductionmentioning

confidence: 81%

“…The C‐X‐C motif chemokine receptor 4 (CXCR4), a CXCR family member specific to response to stromal cell‐derived factor 1α (SDF‐1α), plays a pivotal role in various physiological and pathological processes such as angiogenesis, stem cell trafficking and tumour metastasis 14–16 . Reports have shown that CXCR4 is significantly upregulated after kidney injury, and the sustaining activation of it aggravates the fibrotic responses 17–20 . Our previous studies also found that CXCR4 promotes tubular cell injury and renal fibrosis via activating β‐catenin signalling 21–23 …”

Section: Introductionmentioning

confidence: 99%

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C‐X‐C chemokine receptor type 4 promotes tubular cell senescence and renal fibrosis through β‐catenin‐inhibited fatty acid oxidation

Wu,

Chen,

et al. 2024

J Cellular Molecular Medi

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The prevalence of chronic kidney disease (CKD) is highly increasing. Renal fibrosis is a common pathological feature in various CKD. Previous studies showed tubular cell senescence is highly involved in the pathogenesis of renal fibrosis. However, the inducers of tubular senescence and the underlying mechanisms have not been fully investigated. C‐X‐C motif chemokine receptor 4 (CXCR4), a G‐protein‐coupled seven‐span transmembrane receptor, increases renal fibrosis and plays an important role in tubular cell injury. Whereas, whether CXCR4 could induce tubular cell senescence and the detailed mechanisms have not studied yet. In this study, we adopted adriamycin nephropathy and 5/6 nephrectomy models, and cultured tubular cell line. Overexpression or knockdown of CXCR4 was obtained by injection of related plasmids. We identified CXCR4 increased in injury tubular cells. CXCR4 was expressed predominantly in renal tubular epithelial cells and co‐localized with adipose differentiation‐related protein (ADRP) as well as the senescence‐related protein P16INK4A. Furthermore, we found overexpression of CXCR4 greatly induced the activation of β‐catenin, while knockdown of CXCR4 inhibited it. We also found that CXCR4 inhibited fatty acid oxidation and triggered lipid deposition in tubular cells. To inhibit β‐catenin by ICG‐001, an inhibitor of β‐catenin, could significantly block CXCR4‐suppressed fatty acid oxidation. Taken together, our results indicate that CXCR4 is a key mediator in tubular cell senescence and renal fibrosis. CXCR4 promotes tubular cell senescence and renal fibrosis by inducing β‐catenin and inhibiting fatty acid metabolism. Our findings provide a new theory for tubular cell injury in renal fibrosis.

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