Nitric oxide-induced F-actin disassembly is mediated via cGMP, cAMP, and protein kinase A activation in rat mesangial cells

Glomerular mesangial cells contain actin and myosin, and in analogy to vascular smooth muscle cells, they can contract and relax to regulate the glomerular filtration rate. A key molecule that determines hemodynamic properties is nitric oxide, which is produced by nitric oxide synthase isoenzymes located in individual cells of the kidney. The contractility of mesangial cells is based on the interaction of actin microfilament bundles (F-actin) with myosin. We had the notion that nitric oxide influences the shape change of mesangial cells, so we analyzed the signal transduction involved. Chemically unrelated nitric oxide donors induced F-actin dissolution, which was mediated by cGMP but was unrelated to protein kinase G activation. Actin disassembly was achieved with inhibitors of phosphodiesterase-3 and -4 or forskolin-evoked cAMP generation. We assumed that signal transmission involves activation of protein kinase A, and we went on to attenuate F-actin disassembly by protein kinase A inhibition. In conclusion, we found evidence that nitric oxide triggered F-actin dissolution via cGMP generation, inhibition of cAMP-hydrolyzing phosphodiesterase-3, and subsequent protein kinase A activation. (C) 2001 Elsevier Science.