Critical role of CXCL16 in hypertensive kidney injury and fibrosis.
Recent evidence indicates that inflammation plays a critical role in the initiation and progression of hypertensive kidney disease. However, the signaling mechanisms underlying the induction of inflammation are poorly understood. We found that chemokine (C-X-C motif) ligand 16 (CXCL16) was induced in renal tubular epithelial cells in response to angiotensin II in a nuclear factor-κB-dependent manner. To determine whether CXCL16 plays a role in angiotensin II-induced renal inflammation and fibrosis, wild-type and CXCL16 knockout mice were infused with angiotensin II at 1500 ng/kg per minute for up to 4 weeks. Wild-type and CXCL16 knockout mice had comparable blood pressure at baseline. Angiotensin II treatment led to an increase in blood pressure that was similar between wild-type and CXCL16 knockout mice. CXCL16 knockout mice were protected from angiotensin II-induced renal dysfunction, proteinuria, and fibrosis. CXCL16 deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the kidneys of angiotensin II-treated mice, which was associated with less expression of extracellular matrix proteins. Furthermore, CXCL16 deficiency inhibited infiltration of F4/80(+) macrophages and CD3(+) T cells in the kidneys of angiotensin II-treated mice compared with wild-type mice. Finally, CXCL16 deficiency reduced angiotensin II-induced proinflammatory cytokine expressions in the kidneys. Taken together, our results indicate that CXCL16 plays a pivotal role in the pathogenesis of angiotensin II-induced renal injury and fibrosis through regulation of macrophage and T cell infiltration and bone marrow-derived fibroblast accumulation.
Division of Nephrology, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, BCM395, Houston, TX 77030. yanlinw@bcm.edu.
Yunfeng
Y
Xia
Mark L
ML
Entman
Yanlin
Y
Wang
D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis; D006977:Hypertension, Renal / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009393:Nephritis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; C498926:Cxcl16 protein, mouse; D016207:Cytokines; D016328:NF-kappa B; D000804:Angiotensin II
NF-κB; angiotensin II; chemokines; fibrosis; inflammation