INTERACTION BETWEEN HIGH GLUCOSE AND TGF-BETA IN CELL-CYCLE PROTEIN REGULATIONS IN MDCK CELLS

Transforming growth factor-beta (TGF-beta) may mediate high glucose ef fects in renal cells. Thus, Madin-Darby canine kidney cells were studi ed for the modulation of cell cycle regulatory proteins by high glucos e (27.5 mM) and TGF-beta 1. We showed that unlike other renal cells, T GF-beta 1 mRNA and its bioactivity were not induced by high-glucose cu lture. Furthermore, high glucose per se increased cellular proliferati on without alterations in cell size. High glucose also increased the p ercentage of cells in the G(2)/M phase while decreasing cells in the G (0)/G(1) phase of the cell cycle. In contrast, TGF-beta 1 dose depende ntly (1 to 4 ng/ml) decreased cellular mitogenesis while increasing hy pertrophy in the cells, especially in the presence of high glucose. TG F-beta 1 also increased the percentage of cells arrested in the G(0)/G (1) phase while decreasing cells in the G(2)/M phase of the cell cycle . Regarding two of the cell cycle regulatory proteins, high glucose in creased cdc2 kinase activity and retinoblastoma protein (pRb) phosphor ylation. In contrast, TGF-beta 1 decreased cdc2 kinase activity and pR b phosphorylation, especially in the presence of high glucose. Additio nally, glucose dose dependently (5.5, 16.5, 27.5, and 38.5 mM) increas ed type I and II TGF-beta receptor protein expression. In conclusion. changes in cdc2 kinase activity and pRb phosphorylation were correlate d with high glucose and TGF-beta 1-induced growth effects in a cell cy cle-dependent manner in the Madin-Darby canine kidney cells. Furthermo re, high glucose may potentiate TGF-beta 1-induced effects by enhancin g TGF-beta receptor protein expression.