Glial cell line-derived neurotrophic growth factor (GDNF), a member of the transforming growth factor family, is necessary for renal organogenesis and exhibits changes of expression in models of renal disease. Having demonstrated the participation of nestin-expressing cells in renoprotection, we hypothesized that growth factors and transcription factors similar to those operating in the nervous system should be also operant in the kidney. Using cultured kidney-derived mesenchymal stem cells (MSC) abundantly expressing nestin, we confirmed expression of GDNF by these cells and demonstrated GDNF-induced expression of GDNF. The cellular expression of nestin paralleled that of GDNF expression. Immunohistochemical and Western blot analyses of kidneys obtained from post-ischemic mice showed that expression of GDNF was much enhanced in the renal cortex, a pattern similar to the previously reported expression of nestin. GDNF-treated mice were protected against acute ischemia. To address potential mechanisms of the observed renoprotection, in vitro studies showed that GDNF accelerated MSC migration in a wound healing assay. Hypoxia did not accelerate the motility of MSC and reduced the expression of GDNF in MSC by approximately 2-fold. GDNF was cytoprotective against oxidative stress-induced apoptotic death of MSC. Collectively, these data establish a) an autoregulatory circuit of GDNF-induced GDNF expression in renal MSC; b) induction of GDNF expression in post-ischemic kidneys; c) the ability of exogenous GDNF to ameliorate ischemic renal injury; and d) a possible contribution of GDNF-induced motility and improved survival of MSC to renoprotection.