NH4CL-INDUCED HYPERTROPHY IS MEDIATED BY WEAK BASE EFFECTS AND IS INDEPENDENT OF CELL-CYCLE PROCESSES

Renal hypertrophy occurs in a number of clinical conditions, some of w hich are associated with increases in ambient ammonia concentrations. NH4Cl induces hypertrophy in cultured renal epithelial cells. The pres ent studies examined the mechanism of NH4Cl-induced hypertrophy in NRK -52E cells. Hypertrophy was also induced by methylammonium chloride, a related weak base, but not by tetramethylammonium chloride, a weak ba se analogue that can neither accept nor donate protons. Bafilo-mycin A (1), an inhibitor of vacuolar proton pumps, also induced hypertrophy. Together, these studies suggest that NH4Cl-induced hypertrophy is medi ated by its weak base property, allowing it to enter and alkalinize ac id vesicular compartments. Additional studies demonstrated that NH4Cl- induced hypertrophy is not mediated by modulation of cell cycle proces ses. NH4Cl addition had no effect on the following: c-fos mRNA abundan ce, typically associated with entrance into the cell cycle; cyclin E p rotein abundance, which increases as cells progress through G(1); or p rotein synthesis, which also increases during G(1). In addition, inact ivation of pRB by overexpression of human papilloma virus-16 carrying the E7 gene, which inhibits cell cycle-dependent hypertrophy, had no e ffect on the ability of NH4Cl to induce hypertrophy. Based on these da ta, we postulate that, in hypertrophic conditions associated with incr eased ammoniagenesis, hypertrophy is mediated by vesicular alkalinizat ion and occurs independently of processes that govern progression thro ugh the cell cycle.