MECHANISMS OF RENAL TUBULAR CELL HYPERTROPHY - MITOGEN-INDUCED SUPPRESSION OF PROTEOLYSIS

The combination of epidermal growth factor (EGF) plus transforming gro wth factor-beta 1 (TGF-beta 1) causes hypertrophy in renal epithelial cells. One mechanism contributing to hypertrophy is that EGF induces a ctivation of the cell cycle and increases protein synthesis, whereas T GF-beta 1 prevents cell division, thereby converting hyperplasia to hy pertrophy. To assess whether suppression of proteolysis is another mec hanism causing hypertrophy induced by these growth factors, we measure d protein degradation in primary cultures of proximal tubule cells and in cultured NRK-52E kidney cells. A concentration of 10(-8) M EGF alo ne or EGF plus 10(-10) M TGF-beta 1 decreased proteolysis by similar t o 30%. TGF-beta 1 alone did not change protein degradation. Using inhi bitors, we examined which proteolytic pathway is suppressed. Neither p roteasome nor calpain inhibitors prevented the antiproteolytic respons e to EGF + TGF-beta 1. Inhibitors of lysosomal proteases eliminated th e antiproteolytic response to EGF + TGF-beta 1, suggesting that these growth factors act to suppress lysosomal proteolysis. This antiproteol ytic response was not caused by impaired EGF receptor signaling, since lysosomal inhibitors did not block EGF-induced protein synthesis. We conclude that suppression of lysosomal proteolysis contributes to grow th factor-mediated hypertrophy of cultured kidney cells.