Media acidification inhibits tgfβ-mediated growth suppression in cultured rabbit proximal tubule cells

Chronic metabolic acidosis induces both hyperplastic and hypertrophic renal growth and is associated with progressive loss of renal function. These studies examine the direct effect of media acidification on the growth of rabbit proximal tubule cells in primary culture. The results demonstrate that media acidification has a direct antiproliferative (hypoplastic) effect on both quiescent and mitogen-stimulated [epidermal growth factor (EGF)stimulated] cells and does not induce hypertrophy. This direct antiproliferative effect of acid is associated with inhibition of EGF- induced phosphorylation of the retinoblastoma protein (pRB), which maintains pRB activity and inhibits cell cycle progression from G(i) to S phase. Transforming growth factor-beta (TGF-β) alone has an antiproliferative effect in these cells. TGF-β converts EGF-induced hyperplasia to hypertrophy and inhibits EGF-induced pRB phosphorylation. Media acidification inhibits both the antiproliferative effect of TGF-β and the ability of TGF-β to convert EGF-induced hyperplasia to hypertrophy. This activity is associated with inhibition of TGF-β-mediated retention of pRB in the active, hypophosphorylated state. These results demonstrate that metabolic acidosis has a direct growth-suppressive effect on renal epithelial cells but inhibits the growth-suppressive effects of TGF-β. Inhibition of the antiproliferative effect of cytokines, such as TGF-β, may be responsible for acidosis-induced hyperplasia in vivo.