Glial cell line-derived neurotrophic factor (GDNF) is expressed in the human kidney and is a growth factor for human mesangial cells

Background. Glial cell line-derived neurotrophic factor (GDNF), a recently cloned member of the transforming growth factor-beta (TGF-beta) superfamily , is a potent neurotrophic factor in vitro and in vivo. GDNF is essential f or nephrogenesis and the highest expression of GDNF is found in the develop ing kidney. Increased plasma GDNF levels have recently been documented in p atients with chronic renal failure; the source and role of this increase, h owever, remain unclear. No data are available about the expression of GDNF in human adult kidney or human adult mesangial cell (HMC) cultures. We hypo thesized that GDNF, similar to other members of the TGF-beta superfamily, m ight play a role as a growth factor in the pathogenesis of glomeruloscleros is. Methods. To address this hypothesis, we first investigated (by RT-PCR) the expression of GDNF mRNA and the mRNAs of the GDNF receptors Ret and GFR alp ha-1 in (i) adult human renal cortex and medulla and (ii) in HMC in culture . The results were compared to the expression of these molecules in differe nt developmental stages of the rat kidney. We found that both GDNF and its receptors were expressed in human adult kidney and HMC. Since this finding implicates a role for GDNF beyond nephrogenesis, i.e. in renal physiology/p athophysiology, we investigated the effect of GDNF on HMC growth, i.e. (i) cellular protein synthesis as an index of hypertrophy ([H-3]methionine inco rporation), (ii) DNA synthesis ([H-3]thymidine incorporation) and cell prol iferation (cell numbers) as indices of hyperplasia, and (iii) extracellular matrix synthesis, i.e. collagenous and non-collagenous extracellular prote ins ([H-3]proline incorporation into the collagenase-sensitive and -insensi tive fraction). HMC cultures were used as a surrogate model for the develop ment of glomerulosclerosis. Results. GDNF induced a biphasic growth stimulatory effect in HMC with stim ulation at the lowest concentration used (2 ng/ml) but had no effect at hig her concentrations (20 and 50 ng/ml). In contrast, cellular protein synthes is and extracellular matrix synthesis were significantly and dose-dependent ly increased by GDNF. Conclusions. These results suggest that GDNF, similar to other members of t he TGF-beta superfamily, might play a role as a growth factor for mesangial cells and might thus be a player in the pathogenesis of glomerulosclerosis .