title: Activation of hepatocyte growth factor receptor, c-met, in renal tubules is required for renoprotection after acute kidney injury.
abstract: 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.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Tan
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Lili
authors.initials: L
authors.lastname: Zhou
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002945:Cisplatin / Q000009:adverse effects; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism; D007684:Kidney Tubules / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019859:Proto-Oncogene Proteins c-met / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015427:Reperfusion Injury / Q000150:complications; D015398:Signal Transduction / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D051028:bcl-2-Associated X Protein; D003404:Creatinine; D019859:Proto-Oncogene Proteins c-met; D002945:Cisplatin