L-Arginine Supplementation Antagonizes the Effects of Angiotensin II and Endothelin 1 on Mesangial Cell Proliferation

Proliferation of mesangial cells (MC) is regarded as a precursor to the development of glomerulosclerosis and may be mediated by mitogenic vasoconstrictors such as angiotensin II (ANG-II) and endothelin 1 (ET-1). Dietary supplementation with the nitric oxide (NO) precursor L-arginine has been shown in in vivo models to suppress the development of glomerulosclerosis. We undertook the present study to determine whether L-arginine supplementation in vitro could modulate the mitogenic effects of ANG-II and ET-1 on MC. MC showed significantly greater incorporation of 3Hthymidine compared to control when incubated with 10-6M ANG-II and 10-8M ET-1. Supplementing media with L-arginine to achieve a 10-fold increase in concentration to 4 mM was found to significantly antagonize the mitogenic effect of these agents on MC, an effect that was attenuated by both the NO synthase inhibitor NG-monomethyl-L-arginine as well as the guanylate cyclase inhibitor methylene blue, suggesting that the effect of L-arginine is mediated via cyclic GMP generation. The direct NO generator sodium nitroprusside at 10-5M was also found to suppress MC 3Hthymidine incorporation under ANG-II and ET-1 stimulation, an effect that was also attenuated by coincubation with methylene blue. The protein kinase G inhibitor Rp-8-Br-cGMPS was also found to attenuate the antiproliferative effect of L-arginine. These data suggest that L-arginine supplementation can attenuate the proliferative effect of mitogens such as ANG-II and ET-1 on MC proliferation by a mechanism that appears to require NO and cGMP generation. These findings may in part account for the observed ability of L-arginine supplementation to retard the development of glomerulosclerosis.