title: Ret is critical for podocyte survival following glomerular injury in vivo.
abstract: Podocyte injury and loss directly cause proteinuria and the progression to glomerulosclerosis. Elucidation of the mechanisms of podocyte survival and recovery from injury is critical for designing strategies to prevent the progression of glomerular diseases. Glial cell line-derived neurotrophic factor (GDNF) and its receptor tyrosine kinase, Ret, are upregulated in both nonimmune and immune-mediated in vitro and in vivo models of glomerular diseases. We investigated whether Ret, a known receptor tyrosine kinase critical for kidney morphogenesis and neuronal growth and development, is necessary for glomerular and podocyte development and survival in vivo. Since deletions of both GDNF and Ret result in embryonic lethality due to kidney agenesis, we examined the role of Ret in vivo by generating mice with a conditional deletion of Ret in podocytes (Ret(flox/flox); Nphs2-Cre). In contrast to the lack of any developmental and maintenance deficits, Ret(flox/flox); Nphs2-Cre mice showed a significantly enhanced susceptibility to adriamycin nephropathy, a rodent model of focal segmental glomerulosclerosis. Thus, these findings demonstrated that the Ret signaling pathway is important for podocyte survival and recovery from glomerular injury in vivo.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan; and.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Hou
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan; and.
authors.forename: Victoria
authors.initials: V
authors.lastname: Wu
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan; and.
authors.forename: Gulmohar
authors.initials: G
authors.lastname: Singh
authors.affiliation: Division of Renal Electrolyte and Hypertension, Department of Internal Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Holzman
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan; and cyntsui@umich.edu.
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Tsui
mesh_terms: D000818:Animals; D002470:Cell Survival; D004195:Disease Models, Animal; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism; D007678:Kidney Glomerulus / Q000293:injuries / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009404:Nephrotic Syndrome / Q000151:congenital / Q000378:metabolism; D050199:Podocytes / Q000166:cytology / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse
keywords: glomerulus; kidney injury; neurotrophic growth factor; podocyte