Role of the SDF-1/CXCR4/eNOS Signaling Pathway in Chronic Kidney Disease

Loss of the renal microvasculature is a common feature of almost all forms of chronic kidney disease (CKD). Here we explored the role of the angiogenic chemokine stromal cell-derived factor-1-alpha (SDF-1) and its cognate receptor CXCR4 in experimental and human CKD. CXCR4 was present on endothelial cells and podocytes, while SDF-1 was detectable on podocytes, arteriolar smooth muscle cells, interstitial fibroblasts and occasional endothelial cells. CXCR4 mRNA was elevated in the kidneys of rats with CKD and chronic antagonism of CXCR4 accelerated renal decline and capillary loss. Acute SDF-1 infusion activated glomerular endothelial nitric oxide synthase (eNOS) in vivo, while functional response to SDF-1 was impaired in glomerular endothelial cells derived from eNOS-/- mice. Finally, CXCR4 mRNA was also found to be increased in biopsies of patients with secondary focal segmental glomerulosclerosis. These observations indicate that local eNOS-dependent SDF-1/CXCR4 signaling exerts a compensatory reno-protective effect in the setting of CKD.MAS