Salt-sensitive hypertension and inducible nitric oxide synthase: form-function dichotomy of a coding region mutation, Mutatis mutandis.

The earliest recorded association of dietary salt with blood pressure was reported by Huang Ti Nei Ching Su Wein (ca. 1500 B.C.), who noted that “if large amounts of salt are taken, the pulse will stiffen or harden” (page 82).1 In 1904, Ambard and Beaujard first demonstrated rigorously that dietary salt can increase blood pressure in normal volunteers.2 Throughout the 20th century, the relationship between dietary salt and essential hypertension has been debated; however, evolving epidemiological data3 and recent evidence in nonhuman primates,4 coupled with a growing understanding of the molecular determinants of sodium handling, clearly support the view that certain individuals defined as salt-sensitive5 have a propensity to hypertension when exposed to dietary salt. It is estimated that 50% to 75% of hypertensives are salt-sensitive.5 In the 1960s, Dahl first showed that the hypertensive response to salt was genetically determined.6 He developed two strains of inbred rat, a salt-sensitive (Dahl S) strain in which blood pressure increased in response to dietary salt and a salt-resistant (Dahl R) strain in which blood pressure did not increase in response to dietary salt. These rats have served as the basis for many genetic studies of salt-sensitive hypertension and its end-organ sequelae for many years; yet, until recently, the molecular basis for this genetic sensitivity remained unknown. In this issue of Circulation Research, Ying et al7 provide functional genetic evidence for the molecular basis of salt sensitivity in this animal model. They identified a mutation in the coding sequence of the inducible nitric oxide synthase gene (NOS2) that leads to a gene product that is more rapidly cleared by the proteasome than the wild-type gene product. Functional studies of the expressed protein in conjunction with studies of protein stability were used to support the authors’ conclusion that a lower level of normally functioning inducible nitric oxide synthase accounts for salt-sensitive hypertension in this model. To understand the basis for this study and the interpretation of the results, we must first review the role of nitric oxide (NO) in the renal handling of salt. The normal mammalian response to dietary salt in normotensive individuals is to increase renal NO production, leading to a nitrite-uresis and a natriuresis8; these changes are accompanied by an increase in urinary cGMP and renal vasodilation, indicating that the increased NO is bioactive.9 In salt-sensitive individuals, this response is blunted or absent,8 can be mimicked by selective inhibitors of inducible nitric oxide synthase,10 and can be reversed by L-arginine.11 Moreover, Deng and Rapp12 originally reported in a genetic linkage study that the NOS2 gene cosegregates with blood pressure in the Dahl S rat, a finding that was not subsequently confirmed in rats13 or humans.14 These conflicting results led Deng13 to conclude that NOS2 was not itself the primary genetic determinant of saltsensitive hypertension but a gene that modified the response to dietary salt.9 All three isoforms of nitric oxide synthase are found in the kidney. Neuronal nitric oxide synthase is found principally in the macula densa15 and the inner medullary collecting duct16; endothelial nitric oxide synthase is expressed primarily in endothelial cells of the renal vasculature17; and inducible nitric oxide synthase is constitutively expressed as two structurally distinct forms, a macrophage form and a vascular smooth muscle form,18 with the former found most abundantly in the medullary thick ascending limb and the latter in renal vascular smooth muscle cells.19 In light of its location in the macula densa, neuronal nitric oxide synthase is likely to be involved in tubuloglomerular feedback; however, dietary salt has also been shown to increase neuronal nitric oxide synthase expression acutely in the inner medullary collecting duct of the rat,16 suggesting that NO derived from this enzymatic source may also be responsible, at least in part, for the adaptive renal response to salt loading. In support of this hypothesis, selective infusion of antisense phosphorothioate oligodeoxynucleotides against NOS1 mRNA into the renal medulla or the intramedullary administration of a selective neuronal nitric oxide synthase inhibitor has been shown to produce salt-dependent hypertension.20 In contrast to these acute responses of the neuronal isoform to salt loading, chronic administration of salt leads to reduced expression of neuronal nitric oxide synthase,21 bringing into question its role in the normal, chronic renal homeostatic response to dietary salt. Owing to its location in vascular endothelial cells, endothelial nitric oxide synthase is likely to modulate glomerular resistance, renal blood flow, and glomerular filtration. The expression of this isoform normally increases in response to The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, Mass. Correspondence to Joseph Loscalzo, MD, PhD, Whitaker Cardiovascular Institute, Boston University School of Medicine, 88 E Newton St, Boston, MA 02118-2394. E-mail [email protected] (Circ Res. 2001;89:292-294.) © 2001 American Heart Association, Inc.