Macula Densa Nitric Oxide Synthase 1β Protects against Salt-Sensitive Hypertension

Abstract

Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses a-, b-, and g-splice variants of neuronal nitric oxide synthase 1 (NOS1), and NOS1b expression in the macula densa increases on a high-salt diet. This study tested whether upregulation of NOS1b expression in the macula densa affects sodium excretion and saltsensitive hypertension by decreasing tubuloglomerular feedback responsiveness. Expression levels of NOS1b mRNA and protein were 30-and five-fold higher, respectively, than those of NOS1a in the renal cortex of C57BL/6 mice. Furthermore, macula densa NO production was similar in the isolated perfused juxtaglomerular apparatus of wild-type (WT) and nitric oxide synthase 1a-knockout (NOS1aKO) mice. Compared with control mice, mice with macula densa-specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had a significantly enhanced tubuloglomerular feedback response and after acute volume expansion, significantly reduced GFR, urine flow, and sodium excretion. Mean arterial pressure increased significantly in MD-NOS1KO mice (P,0.01) but not NOS1flox/flox mice fed a high-salt diet. After infusion of angiotensin II, mean arterial pressure increased by 61.6 mmHg in MD-NOS1KO mice versus 32.0 mmHg in WT mice (P,0.01) fed a high-salt diet. These results indicate that NOS1b is a primary NOS1 isoform expressed in the macula densa and regulates the tubuloglomerular feedback response, the natriuretic response to acute volume expansion, and the development of salt-sensitive hypertension. These findings show a novel mechanism for salt sensitivity of BP and the significance of tubuloglomerular feedback response in long-term control of sodium excretion and BP.

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

“…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.…”

“…12,16 Lu et al 12 show that nitric oxide generation by the MD is not affected in NOS1KO mice generated by deletion of NOS1 exon 1 16 and that the BP of these mice is not affected by a high-salt diet. 12 Genome-wide association studies have identified genes that influence only 2% of BP variability and have not identified genes that influence the salt sensitivity of BP. Only a few genes have been found to be associated with salt-sensitive hypertension using candidate gene association studies.…”

“…15 As it turns out, global germline deletion of NOS1 by disruption of exon 1 deletes only the NOS1a isoform. 12,16 Lu et al 12 show that nitric oxide generation by the MD is not affected in NOS1KO mice generated by deletion of NOS1 exon 1 16 and that the BP of these mice is not affected by a high-salt diet. 12 Genome-wide association studies have identified genes that influence only 2% of BP variability and have not identified genes that influence the salt sensitivity of BP.…”

“…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.…”

Nephron‐Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion

“…To our knowledge, no studies have specifically targeted NOS2 within the nephron; while this isoform may prove to play a role within the nephron in blood pressure (BP) control, its low baseline activity and marked induction under pathologic states have made it empirically a less attractive target for examining the role of NOS isoforms in physiological states. Knockout of NOS1 specifically in the macula densa7 increased the hypertensive response to a high‐salt diet, while CD‐specific NOS1 knockout (KO) mice had salt‐sensitive hypertension and an impaired natriuretic response 3. In contrast, CD‐specific deletion of NOS3 did not affect urinary salt excretion and blood pressure in response to high salt intake 8.…”