CXCL16 REGULATES ANGIOTENSIN II-INDUCED INFLAMMATION AND PROTEINURIA

Abstract

Hypertension is a major cause of chronic kidney disease. Recent studies have shown that inflammation plays a critical role in the pathogenesis and progression of hypertensive kidney disease. However, the signaling mechanisms underlying the induction of inflammation are poorly understood. We have found that CXCL16, a recently discovered chemokine, is induced in the kidney in a murine model of angiotensin II (Ang II)-induced hypertension. Therefore, we examined whether CXCL16 regulates inflammatory cell infiltration and renal injury using CXCL16 knockout (CXCL16-KO) mice. Wild-type (WT) and CXCL16-KO mice were treated with Ang II via subcutaneous osmotic minipumps at 1500 ng/kg/min for up to 4 weeks. To accelerate renal injury, all mice were subjected to unilateral nephrectomy and received 1% NaCl in drinking water. WT and CXCL16-KO mice had virtually identical blood pressure at baseline. Ang II treatment led to an increase in blood pressure that is similar between WT and CXCL16-KO mice. Immunohistochemical analysis showed that targeted disruption of CXCL16 inhibits infiltration of F4/80+ macrophages and CD3+ T cells in the kidney of Ang II treated mice compared with WT mice. Real time RT-PCR demonstrated that targeted disruption of CXCL16 reduced gene expression of inflammatory cytokines (IL-1β and TNF-α) in the kidney of Ang II treated mice. Histological analysis revealed that CXCL16 deficiency inhibited Ang II-induced renal injury. Furthermore, targeted deletion of CXCL16 reduced Ang II-induced proteinuria and podocyte loss. In Summary, our results indicate that CXCL16 plays a pivotal role in the development of renal injury and proteinuria through regulation of macrophage and T cell infiltration.