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Binding of the receptor CXCR4 to its ligand stromal cell-derived factor 1 (SDF-1) promotes cell survival and is under the influence of a number of regulatory processes including enzymatic ligand inactivation by endopeptidases such as matrix metalloproteinase 9 (MMP-9). In light of the pivotal role that the SDF-1/CXCR4 axis plays in renal development and in the pathological growth of renal cells, we explored the function of this pathway in diabetic rats and in biopsies from patients with diabetic nephropathy, hypothesizing that the pro-survival effects of CXCR4 in resident cells would attenuate renal injury. Renal CXCR4 expression was observed to be increased in diabetic rats, whereas antagonism of the receptor unmasked albuminuria and accelerated tubular epithelial cell death. In cultured cells, CXCR4 blockade promoted tubular cell apoptosis, up-regulated Bcl-2-associated death promoter, and prevented high glucose/SDF-1-augmented phosphorylation of the pro-survival kinase, Akt. Although CXCR4 expression was also increased in biopsy tissue from patients with diabetic nephropathy, serine 339 phosphorylation of the receptor, indicative of ligand engagement, was unaffected. Coincident with these changes in receptor expression but not activity, MMP-9 was also up-regulated in diabetic nephropathy biopsies. Supporting a ligand-inactivating effect of the endopeptidase, exposure of cultured cells to recombinant MMP-9 abrogated SDF-1 induced Akt phosphorylation. These observations demonstrate a potentially reno-protective role for CXCR4 in diabetes that is impeded in its actions in the human kidney by the coincident up-regulation of ligand-inactivating endopeptidases. Therapeutically intervening in this interplay may limit tubulointerstitial injury, the principal determinant of renal decline in diabetes.