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Hepatocyte Growth Factor Receptor in Acute Tubular Necrosis

RALPH RABKIN^*,*, FERNANDO FERVENZA^*,*, TANNY TSAO^*,*, RICHARD SIBLEY, MICHAEL FRIEDLAENDER^*,*, FAY HSU^*,*, CHARLES LASSMAN, MICHAEL HAUSMANN^*,*, PHIL HUIE and RALPH H. SCHWALL

^* Research Service Veterans Affairs Palo Alto Health Care System, Stanford University, Palo Alto, California
^* Department of Medicine, Stanford University, Palo Alto, California
Department of Pathology, Stanford University, Palo Alto, California
Department of Molecular Oncology, Genentech Inc., South San Francisco, California

Correspondence to Dr. Ralph Rabkin, VAPAHCS (111R), 3801 Miranda Avenue, Palo Alto, CA 94304. Phone: 650-858-3985; Fax: 650-849-0213; E-mail: rabkin{at}leland.stanford.edu

Abstract. In acute tubular necrosis, there are early transient increases in circulating and local bioactive hepatocyte growth factor (HGF) levels and renal HGF receptor (c-MET) gene expression. It has therefore been suggested that endogenous HGF may play a role in initiating renal repair. To test this hypothesis, changes in the levels, activity, and anatomic distribution of c-MET protein were characterized in relation to the onset and localization of DNA synthesis in kidneys of rats with ischemia-induced acute tubular necrosis. Whole-kidney c-MET protein levels were significantly increased in the injured kidneys 12 h after injury and rose to a maximum after 1 d, exceeding the control values by sevenfold. Eight days after injury, c-MET levels, although decreasing, were still elevated above control values. An increase in the levels of activated c-MET, i.e., tyrosine-phosphorylated c-MET, was also evident as early as 12 h after injury. Histologic analyses demonstrated that the increase in c-MET immunoreactivity was most marked in the most severely damaged nephron segments in the outer medulla. In injured proximal tubules, the receptor was redistributed from an apical location to an intracellular location. DNA synthesis was increased in the injured kidneys, especially in the outer medulla, where the increase in c-MET protein levels was most prominent. The increase in DNA synthesis was first detected 12 h after the initial increase in activated c-MET levels. It is concluded that the early increases in the levels of c-MET protein and activated receptor support the hypothesis that HGF participates in the initiation of renal regeneration. In addition, the persistent elevation of c-Met protein levels suggests that prolonged and even late treatment with HGF may be of therapeutic value

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