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J Am Soc Nephrol 14:620-630, 2003
© 2003 American Society of Nephrology

Production of the Novel Mesangial Autocrine Growth Factors GDNF and IL-10 Is Regulated by the Immunomodulator AS101

Yona Kalechman*, Benjamin Sredni*, Talia Weinstein{dagger}, Ilya Freidkin*, Ana Tobar{dagger}, Michael Albeck* and Uzi Gafter{dagger}

*C.A.I.R. Institute, Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel; and {dagger}Departments of Nephrology and Pathology, Rabin Medical Center, Petah Tikva, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Correspondence to Prof. B. Sredni, C.A.I.R. Institute, Faculty of Life Sciences, Bar Ilan University, Ramat Gan, 52900 Israel. Phone: 972-3-5318250; Fax: 972-3-6356041;

ABSTRACT. 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-{kappa}B were found to mediate GDNF-induced MC mitogenesis. This pathway also mediates GDNF-induced decrease in the cyclin-dependent kinase inhibitor p27kip1 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. E-mail: srednib@mail.biu.ac.il




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