Nitric oxide modulates mechanical strain-induced activation of p38 MAPK inmesangial cells

Mesangial cells (MC), grown on extracellular matrix (ECM) protein-coated pl ates and stretched, proliferate and produce ECM, recapitulating in vivo res ponses to increased glomerular capillary pressure (Pgc). Transduction of st rain involves mitogen-activated protein kinases (MAPK), and we have shown t hat p38 MAPK is activated by strain in MC. Because in vivo studies show tha t nitric oxide (NO) in the remnant kidney limits glomerular injury without reducing Pgc, we studied whether NO attenuated stretch-induced p38 activati on in MC. Increasing p38 activation occurred with increasing stretch, maxim ally at 10 min at 227-kPa vacuum. Cyclic strain increased nuclear transloca tion of phosphorylated p38 by immunofluorescent microscopy and nuclear prot ein binding to nuclear factor-kappa B (NF-kappa B) consensus sequences by m obility shift assay. Both events were largely abrogated by the p38 inhibito r SB-203580. The NO donors 3-morpholinosydnonimine, S-nitroso-N-acetylpenic illamine, and 8-bromoguanosine 3', 5'-cyclic monophosphate, a stable cGMP a nalog, prevented p38 activation and nulcear translocation. Thus strain indu ces p38 activity and translocation to the nucleus and p38-dependent increas es in nuclear protein binding to NF-kappa B. This pathway is attenuated by the NO donors or a cGMP analog.