Hepatocyte growth factor is a pleiotrophic protein that promotes injury repair and regeneration in multiple organs. Here, we show that after acute kidney injury (AKI), the HGF receptor, c-met, was induced predominantly in renal tubular epithelium. To investigate the role of tubule-specific induction of c-met in AKI, we generated conditional knockout mice, in which the c-met gene was specifically disrupted in renal tubules. These Ksp-met-/- mice were phenotypically normal and had no appreciable defect in kidney morphology and function. However, in AKI induced by cisplatin or ischemia/reperfusion injury, the loss of tubular c-met substantially aggravated renal injury. Compared with controls, Ksp-met-/- mice displayed higher serum creatinine, more severe morphologic lesions, and increased apoptosis, which was accompanied by an increased expression of Bax and Fas ligand and decreased phosphorylation/activation of Akt. In addition, ablation of c-met in renal tubules promoted chemokine expression and renal inflammation after AKI. Consistently, ectopic expression of hepatocyte growth factor in vivo protected the kidneys against AKI in control mice, but not in Ksp-met-/- counterparts. Thus, our results suggest that tubule-specific c-met signaling is crucial in conferring renal protection after AKI, primarily by its anti-apoptotic and anti-inflammatory mechanisms.