Do You Want to Ditch Sodium? Meet Nitric Oxide Synthase 1β at the Macula Densa

Abstract

Hypertension is present in about 40% of the world's population, and it is responsible for 12.8% of total deaths. 1 However, these statistics do not include normotensive individuals who are salt (NaCl)-sensitive. 2 Salt sensitivity, independent of BP, is a risk factor for not only cardiovascular morbidity and mortality but also other diseases, including metabolic syndrome. [2][3][4] Several organs, including the kidney, participate in whole-body sodium homeostasis and BP regulation. 5 The importance of the kidney in BP regulation is supported by renal transplantation studies in humans and rodents. 6,7 The inability of the kidney to excrete a sodium load would result in a positive sodium balance, an increase in BP, and eventually, hypertension.Renal autoregulation maintains renal blood flow and GFR, independent of perfusion pressure between 80 and 180 mmHg, and protects the kidney from hypertensive injury. 5,8 This is afforded by myogenic and macula densa (MD) tubuloglomerular feedback responses. Several vasoactive agents have been proposed to mediate or modulate tubuloglomerular feedback, including nitric oxide and angiotensin II. 5,8 Neuronal nitric oxide synthase (nNOS) is expressed in the MD, and direct blockade by specific inhibitors increases tubuloglomerular feedback. 9 However, the inhibition of nitric oxide synthesis modulates but does not impair the myogenic vasoconstriction of the afferent arteriole in spontaneously hypertensive rats. 10 Lu et al. 11 have previously reported that splice variants of nNOS in MD cells may be important in the regulation of tubuloglomerular feedback during salt loading.In this report, Lu et al. 12 extend the aforementioned study by testing the hypothesis that nitric oxide synthase 1b (NOS1b) may be the salt-sensitive isoform of NOS1 in the MD that modulates tubuloglomerular feedback response, promotes sodium excretion, and protects against the development of salt-sensitive hypertension. To test this hypothesis, Lu et al. 12 deleted all of the NOS1 splice variants specifically from the MD of C57Bl/6 mice. Compared with control wild-type mice, mice with MD-specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had enhanced tubuloglomerular feedback response after acute volume expansion, and their BPs were increased by a high-salt diet. Relative to wild-type mice, MD-NOS1KO mice on a high-salt diet also had greater BP responses to chronic infusion of angiotensin II. Because MD nitric oxide production was similar in the isolated perfused juxtaglomerular apparatus of wild-type and NOS1a-knockout mice, these studies suggest that the phenotype that results from MD-NOS1KO is caused by NOS1b. Although a more direct evaluation of the specific NOS1 isoform in the regulation of tubuloglomerular feedback would have been MDspecific deletion of NOS1b, these elegant experiments support the conclusion that NOS1b is the salt-sensitive isoform of NOS1 expressed in the MD that regulates the tubuloglomerular feedback response and protects against the development of saltsensitive h...