TUMOR-NECROSIS-FACTOR-ALPHA ACTIVATES SOLUBLE GUANYLATE-CYCLASE IN BOVINE GLOMERULAR MESANGIAL CELLS VIA AN L-ARGININE DEPENDENT MECHANISM

Endothelium-derived nitric oxide (NO) causes vasodilatation by activating soluble guanylate cyclase, and glomerular mesangial cells respond to NO with elevations of intracellular guanosine 3',5'- cyclic monophosphate (cGMP). We explored whether mesangial cells can be stimulated to produce NO and whether NO modulates mesangial cell function in an autocrine or paracrine fashion. Tumor necrosis factor alpha (TNF-α) raised mesangial cell cGMP levels in a time- and concentrationdependent manner (threshold dose 1 ng/ml, IC50 13.8 ng/ml, maximal response 100 ng/ml). TNF-α-induced increases in mesangial cGMP content were evident at 8 h and maximal at 18- 24 h. The TNF-α-induced stimulation of mesangial cell cGMP production was abrogated by actinomycin D or cyloheximide suggesting dependence on new RNA or protein synthesis. Hemoglobin and methylene blue, both known to inhibitNOaction, dramatically reduced TNF-α- induced mesangial cell cGMP production. Superoxide dismutase, known to potentiate NO action, augmented the TNF-a-induced effect. Ng-monomethyl-L-arginine (L-NMMA) decreased cGMP levels in TNF-α-treated, but not vehicle-treated mesangial cells in a concentration-dependent manner (ICso 53 PM). L-arginine had no effect on cGMP levels in control or TNF-a-treated mesangial cells but reversed L-NMMA-induced inhibition. Interleukin 1/3 and lipopolysaccharide (LPS), but not interferon γ, also increased mesangial cell cGMP content. Transforming growth factor β1 blunted the mesangial cell response to TNF-α. TNF-α-induced L-arginine-dependent increases in cGMP were also evident in bovine renal artery vascular smooth muscle cells, COS-1 cells, and 1502 human fibroblasts. These findings suggest that TNF-α induces expression in mesangial cell ofan enzyme(s) involved in the formation of L-arginine-derived NO. Moreover, the data indicate that NO acts in an autocrine and paracrine fashion to activate mesangial cell soluble guanylate cyclase. Cytokine-induced formation of NO in mesangial and vascular smooth muscle cells may be implicated in the pathogenesis of septic shock. © 1990, Rockefeller University Press., All rights reserved.