The CXCR4-AT1 axis plays a vital role in glomerular injury via mediating the crosstalk between podocyte and mesangial cell.
Transl Res
; 264: 15-32, 2024 02.
Article
em En
| MEDLINE
| ID: mdl-37696390
ABSTRACT
Glomeruli stand at the center of nephrons to accomplish filtration and albumin interception. Podocytes and mesangial cells are the major constituents in the glomeruli. However, their interdependency in glomerular injury has rarely been reported. Herein, we investigated the role of C-X-C chemokine receptor type 4 (CXCR4) in mediating the crosstalk between podocytes and mesangial cells. We found CXCR4 and angiotensin II (AngII) increased primarily in injured podocytes. However, type-1 receptor of angiotensin II (AT1) and stromal cell-derived factor 1α (SDF-1α), a ligand of CXCR4, were evidently upregulated in mesangial cells following the progression of podocyte injury. Ectopic expression of CXCR4 in 5/6 nephrectomy mice increased the decline of renal function and glomerular injury, accelerated podocyte injury and mesangial cell activation, and initiated CXCR4-AT1 axis signals. Additionally, treatment with losartan, an AT1 blocker, interrupted the cycle of podocyte injury and mesangial matrix deposition triggered by CXCR4. Podocyte-specific ablation of CXCR4 gene blocked podocyte injury and mesangial cell activation. In vitro, CXCR4 overexpression induced oxidative stress and renin angiotensin system (RAS) activation in podocytes, and triggered the communication between podocytes and mesangial cells. In cultured mesangial cells, AngII treatment induced the expression of SDF-1α, which was secreted into the supernatant to further promote oxidative stress and cell injury in podocytes. Collectively, these results demonstrate that the CXCR4-AT1 axis plays a vital role in glomerular injury via mediating pathologic crosstalk between podocytes and mesangial cells. Our findings uncover a novel pathogenic mechanism by which the CXCR4-AT1 axis promotes glomerular injury.
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Base de dados:
MEDLINE
Assunto principal:
Podócitos
Limite:
Animals
Idioma:
En
Revista:
Transl Res
Assunto da revista:
MEDICINA
/
TECNICAS E PROCEDIMENTOS DE LABORATORIO
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China