Organ cross-talk exists in many diseases of the human and animal models of human diseases. Recent study had demonstrated that inflammatory mediators can cause acute kidney injury and neutrophil infiltration in a mouse model of DSS-colitis. However, the chemokines and their receptors that may mediate distant organ effects in colitis are unknown. We hypothesized that KC/IL-8 receptor CXCR2 mediates DSS-colitis induced acute kidney injury. Consistent with our hypothesis, WT mice developed severe colitis with DSS treatment which was associated with inflammatory cytokine and chemokine expression and neutrophil infiltration in the colon. DSS-colitis in WT was accompanied by acute kidney injury and enhanced expression of inflammatory cytokines in the kidney. However, CXCR2 knockout mice were protected against DSS-colitis as well as acute kidney injury. Moreover, the expression of cytokines and chemokines and neutrophil infiltration was blunted in CXCR2 KO mice in the colon and kidney. Administration of recombinant KC exacerbated DSS-colitis induced acute kidney injury. Our results suggest that KC/IL-8 and its receptor CXCR2 are critical and major mediators of organ cross talk in DSS colitis and neutralization of CXCR2 will help to reduce the incidence of acute kidney injury due to ulcerative colitis and Chron's disease in humans.