Production of the novel mesangial autocrine growth factors GDNF and IL-10 is regulated by the immunomodulator AS101.
Mesangial cell (MC) proliferation is essential for the pathogenesis and progression of various glomerular diseases. This study shows that glial cell line-derived neurotrophic factor (GDNF) and IL-10 are mesangial autocrine growth factors that play a pivotal role in rat MC proliferation in vitro. Downstream targets of GDNF signaling and their role in MC hyperplasia are identified. The phosphatidylinositol 3-kinase (PI3K) pathway and its downstream target NF-kappaB were found to mediate GDNF-induced MC mitogenesis. This pathway also mediates GDNF-induced decrease in the cyclin-dependent kinase inhibitor p27(kip1) expression, resulting in the increased formation of cyclin D1/cdk4 and cyclin E/cdk2 complexes, followed by hyperphosphorylation of retinoblastoma, a key event for G1 to S phase progression. IL-10 appears to be a more potent MC growth factor that negatively regulates GDNF expression. Indeed, its inhibition by the nontoxic tellurium anti-IL-10 compound, ammonium trichloro(dioxoethylene-o,o') tellurate (AS101), extensively decreased MC clonogenicity despite GDNF upregulation. Identification of the mesangial GDNF and IL-10 pathways as critical mediators of mesangial cell proliferation may provide another target for therapeutic intervention in certain glomerular diseases. In vivo animal studies using AS101, currently undergoing phase II clinical trials on cancer patients, are warranted to determine its potential in the management of glomerular diseases associated with mesangial cell proliferation.
Kalechman
Yona
Y
C.A.I.R. Institute, Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
Sredni
Benjamin
B
Weinstein
Talia
T
Freidkin
Ilya
I
Tobar
Ana
A
Albeck
Michael
M
Gafter
Uzi
U
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000276:immunology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D005030:Ethylenes / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005920:Glomerular Mesangium / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D000276:Adjuvants, Immunologic; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins; D005030:Ethylenes; D051100:Glial Cell Line-Derived Neurotrophic Factor; D016753:Interleukin-10; D016328:NF-kappa B; D009414:Nerve Growth Factors; D019869:Phosphatidylinositol 3-Kinases; D025521:Tumor Suppressor Proteins; D018631:ras Proteins; C493958:Cdkn1a protein, rat; C493962:Cdkn1b protein, rat; C495041:Gdnf protein, rat; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate