C-X-C Chemokine Receptor Type 4 Plays a Crucial Role in Mediating Oxidative Stress-Induced Podocyte Injury

Abstract

In mouse model of adriamycin nephropathy (ADR), CXCR4 expression was significantly induced in podocytes as early as 3 days. This was accompanied by an increased upregulation of oxidative stress in podocyte, as demonstrated by malondialdehyde assay, nitrotyrosine staining and secretion of 8-hydroxy-2'-deoxyguanosine in urine, and induction of NOX2 and NOX4, major subunits of NADPH oxidase. CXCR4 was also induced in human kidney biopsies with proteinuric kidney diseases and colocalized with advanced oxidation protein products (AOPPs), an established oxidative stress trigger. Using cultured podocytes and mouse model, we found that AOPPs induced significant loss of podocyte marker Wilms tumor 1 (WT1), nephrin, and podocalyxin, accompanied by upregulation of desmin both in vitro and in vivo. Furthermore, AOPPs worsened proteinuria and aggravated glomerulosclerosis in ADR. These effects were associated with marked activation of SDF-1α/CXCR4 axis in podocytes. Administration of AMD3100, a specific inhibitor of CXCR4, reduced proteinuria and ameliorated podocyte dysfunction and renal fibrosis triggered by AOPPs in mice. In glomerular miniorgan culture, AOPPs also induced CXCR4 expression and downregulated nephrin and WT1. Innovation and Conclusion: These results suggest that chemokine receptor CXCR4 plays a crucial role in mediating oxidative stress-induced podocyte injury, proteinuria, and renal fibrosis. CXCR4 could be a new target for mitigating podocyte injury, proteinuria, and glomerular sclerosis in proteinuric chronic kidney disease. Antioxid. Redox Signal. 27, 345-362.

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

“…As a G‐protein–coupled seven‐span transmembrane receptor, C‐X‐C motif chemokine receptor 4 (CXCR4) serves as the key molecule to leash haematopoietic stem cells to quiescence in bone marrow . Recently, some reports indicate CXCR4 plays a crucial role in various types of CKD such as rapidly progressive glomerulonephritis (RPGN), IgA nephropathy (IgAN), lupus and tubulo‐interstitial nephritis . Although CXCR4 exists in various types of cells such as podocytes, macrophages and endothelial cells, it is predominantly localized in tubular cells, especially proximal tubular epithelial cells .…”

“…Recently, some reports indicate CXCR4 plays a crucial role in various types of CKD such as rapidly progressive glomerulonephritis (RPGN), IgA nephropathy (IgAN), lupus and tubulo‐interstitial nephritis . Although CXCR4 exists in various types of cells such as podocytes, macrophages and endothelial cells, it is predominantly localized in tubular cells, especially proximal tubular epithelial cells . Through the binding of CXC chemokine ligand 12 (CXCL12; stromal cell–derived factor 1 (SDF‐1)), CXCR4 exerts multiple effects in cell survival, differentiation and injury .…”

“…Although CXCR4 exists in various types of cells such as podocytes, macrophages and endothelial cells, it is predominantly localized in tubular cells, especially proximal tubular epithelial cells . Through the binding of CXC chemokine ligand 12 (CXCL12; stromal cell–derived factor 1 (SDF‐1)), CXCR4 exerts multiple effects in cell survival, differentiation and injury . However, the role of CXCR4 in renal tubular cell injury and the underlying mechanisms remain poorly understood.…”

The emerging role of cellular senescence in renal diseases

“…1 The inhibition of DNA replication and rupture of its double-strand are typical features of cellular senescence. 3 Cellular senescence plays a critical role in normal embryonic development in humans and animals and is involved in wound healing. 3 Cellular senescence plays a critical role in normal embryonic development in humans and animals and is involved in wound healing.…”

“…2 There are many causes of cellular senescence including genomic damage, activation of oncogenes and inflammation. 3 Cellular senescence plays a critical role in normal embryonic development in humans and animals and is involved in wound healing. 4 However, enhanced cellular senescence is also found in multiple organs in the process of ageing or after injury, suggesting that there should be different effects of cellular senescence depending on the pathophysiological context.…”