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.