Nitric oxide and the kidney
- Philip A Marsden, MD
Philip A Marsden, MD
- Professor of Medicine
- Vice-Chair, Department of Medicine at the University of Toronto, Research
- Oreopoulos-Baxter Division Director of Nephrology at the University of Toronto
Nitric oxide (NO) has a major role as a messenger molecule in most human organ systems . In the blood vessel wall, basal and calcium-agonist stimulated release of NO largely accounts for the bioactivity of endothelium-derived relaxing factor (EDRF) . In the kidney, as well as other solid organs, physiologic concentrations of NO function as a tonic vasodilator, working essentially instantaneously . However, higher concentrations can be toxic, damaging cellular constituents (such as DNA) and inducing hypotension in those with sepsis .
NO, a molecular gas, is formed by the action of one of three isoforms of nitric oxide synthase (NOS). The isoforms were named based upon the cell types in which they were first isolated: neuronal NOS (nNOS or NOS1); inducible or macrophage NOS (iNOS, NOS2); and endothelial NOS (eNOS, NOS3) . All three enzymes, which are cytochrome P450-like proteins, facilitate the addition of the guanidino nitrogen of the amino acid arginine to molecular oxygen, producing NO and water.
The expression of the three NOS isoforms differs, resulting in varying amounts of NO production. In general, eNOS and nNOS are constitutively active, producing relatively low levels of NO, with the output varying with changes in the intracellular calcium concentration. By comparison, the transcriptional regulation of iNOS can be markedly induced, particularly by inflammatory cytokines, resulting in extremely large amounts of NO.
NO is a paracrine mediator that works differently from endocrine mediators, such as angiotensin II and antidiuretic hormone. NO, which is produced and released by individual cells, readily penetrates the biological membranes of neighboring cells, modulating a number of signaling cascades. Since it has an extremely short half-life, it exerts its effects locally and transiently.
The most recognized cellular target of NO is heme-containing soluble guanylate cyclase. The stimulation of this compound enhances the synthesis of cyclic GMP (cGMP) from guanosine triphosphate (GTP), increasing the cytosolic levels of cGMP. The effects of NO can be enhanced by inhibiting the breakdown of cGMP, a process catalyzed by a family of phosphodiesterases.
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