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 for nephrogenesis and the highest expression of GDNF is found in the developing kidney. Increased plasma GDNF levels have recently been documented in patients with chronic renal failure; the source and role of this increase, however, remain unclear. No data are available about the expression of GDNF in human adult kidney or human adult mesangial cell (HMC) cultures. We hypothesized that GDNF, similar to other members of the TGF-beta superfamily, might play a role as a growth factor in the pathogenesis of glomerulosclerosis.


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 GFRalpha-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 different 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/pathophysiology, we investigated the effect of GDNF on HMC growth, i.e. (i) cellular protein synthesis as an index of hypertrophy ([(3)H]methionine incorporation), (ii) DNA synthesis ([(3)H]thymidine incorporation) and cell proliferation (cell numbers) as indices of hyperplasia, and (iii) extracellular matrix synthesis, i.e. collagenous and non-collagenous extracellular proteins ([(3)H]proline incorporation into the collagenase-sensitive and -insensitive fraction). HMC cultures were used as a surrogate model for the development of glomerulosclerosis.


RESULTS
GDNF induced a biphasic growth stimulatory effect in HMC with stimulation at the lowest concentration used (2 ng/ml) but had no effect at higher concentrations (20 and 50 ng/ml). In contrast, cellular protein synthesis and extracellular matrix synthesis were significantly and dose-dependently increased by GDNF.


CONCLUSIONS
These results suggest that GDNF, similar to other members of the 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.
Orth
S R
SR
Departments of Internal Medicine and. Anatomy and Cell Biology III, Ruperto Carola University Heidelberg, Heidelberg, Germany.
Ritz
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E
Suter-Crazzolara
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D000375:Aging / Q000378:metabolism; D000818:Animals; D002452:Cell Count / Q000187:drug effects; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D029721:Drosophila Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D005920:Glomerular Mesangium / Q000166:cytology* / Q000378:metabolism; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000254:growth & development / Q000378:metabolism*; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D014176:Protein Biosynthesis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism
D029721:Drosophila Proteins; C495039:GDNF protein, human; C494987:GFRA1 protein, human; C495041:Gdnf protein, rat; C494989:Gfra1 protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006133:Growth Substances; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D003094:Collagen; D004247:DNA; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C495001:Ret protein, rat