Glial cell line-derived neurotrophic
growth factor (GDNF), a member of the
transforming growth factor family, is necessary for renal organogenesis and exhibits changes in expression in models of renal disease.
Nestin is an intermediate filament
protein originally believed to be a marker of neuroepithelial stem cells and recently proposed as a marker of mesenchymal stem cells (MSC). Having demonstrated the participation of
nestin-expressing cells in renoprotection during acute renal
ischemia, we hypothesized that
growth factors and
transcription factors similar to those operating in the nervous system should be also operant in the kidney and may be induced after noxious stimuli, such as an ischemic episode. Using cultured kidney-derived MSC, which abundantly express
nestin, we confirmed expression of
GDNF by these cells and demonstrated the
GDNF-induced expression of
GDNF. The cellular expression of
nestin paralleled that of
GDNF: serum
starvation decreased the expression, whereas application of
GDNF resulted in a dose-dependent increase in
nestin expression. Immunohistochemical and Western blot analyses of kidneys obtained from control and postischemic mice showed that expression of
GDNF was much enhanced in the renal cortex, a pattern similar to the previously reported expression of
nestin. Based on the observed
GDNF-induced
GDNF expression, we next explored the effect of supplemental
GDNF administered early after
ischemia on renal function postischemia.
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, but rather slightly reduced, the motility of MSC and reduced the expression of
GDNF in MSC by approximately twofold. Furthermore,
GDNF was cytoprotective against oxidative stress-induced apoptotic death of MSC. Collectively, these data establish 1) an autoregulatory circuit of
GDNF-induced
GDNF expression in renal MSC; 2) induction of
GDNF expression in postischemic kidneys; 3) the ability of exogenous
GDNF to ameliorate ischemic renal injury; and 4) a possible contribution of
GDNF-induced motility and improved survival of MSC to renoprotection.