Deletion of the Met receptor in the collecting duct decreases renal repair following ureteral obstruction

Hepatocyte growth factor and its receptor, Met, activate biological pathways necessary for repair and regeneration following kidney injury. The Met receptor is expressed in multiple cell types within the kidney, each of which is capable of regulating fibrotic responses. To specifically address the role of the Met receptor in the adult collecting duct during renal injury, a conditional knockout mouse (Metfl/fl;HoxB7-Cre) was generated and tested using unilateral ureteral obstruction, a model of nephron injury, fibrosis, and repair. Following obstruction in these mice there was increased expression of collagens I and IV along with plasminogen activator inhibitor 1, a known regulator of matrix degradation, compared to ureteral obstructed non-flox littermates. There were trends toward increased interstitial fibrosis, infiltration of the interstitium, and acute tubular necrosis in the knockout mice despite similar degrees of hydronephrosis to the control littermates. The Metfl/fl;HoxB7-Cre mice; however, had reduced tubular cell proliferation and kidney regenerative capacity after release of the obstruction, thus leading to diminished functional recovery. We suggest that Met receptor signaling in the collecting duct acts as a major regulator of cell survival and propagation of the repair process with a possible secondary role to diminish inflammatory and fibrotic responses.