C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Abstract

Chronic kidney disease (CKD) has a high prevalence worldwide. Renal fibrosis is the common pathological feature in various types of CKD. However, the underlying mechanisms are not determined. Here, we adopted different CKD mouse models and cultured human proximal tubular cell line to examine the expression of C-X-C motif chemokine receptor 4 (CXCR4) and β-catenin signalling, as well as their relationship in renal fibrosis. In CKD mice and humans with a variety of nephropathies, CXCR4 was dramatically up-regulated in tubules, with a concomitant activation of β-catenin. CXCR4 expression level was positively correlated with the expression of β-catenin target MMP-7. AMD3100, a CXCR4 receptor blocker, and gene knockdown of CXCR4 significantly inhibited the activation of JAK/STAT and β-catenin signalling, protected against tubular injury and renal fibrosis. CXCR4-induced renal fibrosis was inhibited by treatment with ICG-001, an inhibitor of β-catenin signalling. In HKC-8 cells, overexpression of CXCR4 induced activation of β-catenin and deteriorated cell injury. These effects were inhibited by ICG-001. Stromal cell-derived factor (SDF)-1α, the ligand of CXCR4, stimulated the activation of JAK2/STAT3 and JAK3/STAT6 signalling in HKC-8 cells. Overexpression of STAT3 or STAT6 decreased the abundance of GSK3β mRNA. Silencing of STAT3 or STAT6 significantly blocked SDF-1α-induced activation of β-catenin and fibrotic lesions. These results uncover a novel mechanistic linkage between CXCR4 and β-catenin activation in renal fibrosis in association with JAK/STAT/GSK3β pathway. Our studies also suggest that targeted inhibition of CXCR4 may provide better therapeutic effects on renal fibrosis by inhibiting multiple downstream signalling cascades.

Chemokine Therapy in Cats With Experimental Renal Fibrosis and in a Kidney Disease Pilot Study

“…There are published studies that seem to contradict our results and dispute the beneficial effects of CXCL12 on kidney regeneration ( 54 ), renal function and fibrosis ( 55 , 56 ), and collagen synthesis in different tissues and organs. These studies report inflammatory effects of serum CXCL12 in various disease states ( 57 , 58 ), to include malignancy ( 59 ), and that the CXCL12/CXCR4 mechanism may be directly involved in renal carcinoma ( 59 ).…”

“…These studies report inflammatory effects of serum CXCL12 in various disease states ( 57 , 58 ), to include malignancy ( 59 ), and that the CXCL12/CXCR4 mechanism may be directly involved in renal carcinoma ( 59 ). Additionally, other in vitro cell culture studies report CXCL12/CXCR4 axis-mediated kidney pathology and activation of collagen synthesis ( 56 , 60 , 61 ). However, these studies focus on the secretion of physiologic CXCL12 that Ray et al showed to form dimers in physiologic conditions and high concentrations that more efficiently activate pathways leading to pathology and malignancy and inhibit chemotaxis ( 32 , 62 , 63 ).…”

Klotho retards renal fibrosis through targeting mitochondrial dysfunction and cellular senescence in renal tubular cells

“…Western blot analyses were performed as previously reported (Liu et al, 2020; Zhou et al, 2019). Briefly, the kidney tissue or HKC‐8 cells were extracted the protein in lysis buffer.…”

STX‐0119, a novel STAT3 dimerization inhibitor, prevents fibrotic gene expression in a mouse model of kidney fibrosis by regulating Cxcr4 and Ccr1 expression

“…Thus, we suggest that the preventive effects of STX‐0119 on kidney fibrotic genes are partially mediated by Cxcr4 downregulation in kidney fibroblasts. Recently, Liu et al reported the upregulation of Cxcr4 in tubular cells in kidneys from patients with IgA nephropathy, rapidly progressing glomerulonephritis, and FSGS (Liu et al., 2020). Therefore, Cxcr4 blockade may be effective not only in animal models but also in human fibrotic kidneys.…”