Mechanism of atrial natriuretic factor-induced inhibition of rat mesangial cell mitogenesis

Recent observations suggest that atrial natriuretic factor (ANF) may have growth-inhibitory activity. The present studies were performed to further define this action in rat mesangial cells (which have both biological and clearance ANF receptors) and in 3T3 fibroblasts (which have only clearance ANF receptors). Both cell types were made quiescent by removal of serum and then reactivated by exposure to a serum-free defined medium. ANF inhibited [3H]thymidine uptake in a dose-dependent manner in mesangial cells (half-maximal response 10(-11) M; 47% maximal inhibitory effect) but had no effect in 3T3 fibroblasts. Exogenous 8-bromoguanosine 3',5'-cyclic monophosphate (0.1 mM) inhibited [3H]thymidine uptake by 33% in mesangial cells but had no effect in 3T3 fibroblasts. Counts in mesangial cells exposed to 0.1 mM sodium nitroprusside, which stimulates guanosine 3',5'-cyclic monophosphate (cGMP), were inhibited by 76%. However, this represented a toxic effect, because excessive trypan blue uptake was noted in this condition. Mesangial cell number after 3 days of logarithmic proliferation was reduced by 33% in cells incubated with 1.0 nM ANF compared with vehicle. Incubation of mesangial cell monolayers with ANF caused a concentration-dependent increase in intracellular cGMP accumulation. Threshold responses occurred at concentrations one order of magnitude greater than that resulting in the antimitogenic action. In 3T3 fibroblast monolayers exposed to ANF, cGMP accumulation occurred but was markedly attenuated compared with mesangial cells.(ABSTRACT TRUNCATED AT 250 WORDS)