Macula densa nitric oxide synthase 1b protects against salt-sensitive hypertension

Yan Lu, Jin Wei, David E. Stec, Richard J. Roman, Ying Ge, Liang Cheng, Eddie Y. Liu, Jie Zhang, Pernille B.Laerkegaard Hansen, Fan Fan, Luis A. Juncos, Lei Wang, Jennifer Pollock, Paul L. Huang, Yiling Fu, Shaohui Wang, Ruisheng Liu

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


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 32.0mmHg in WT mice (P,0.01) fed a high-salt diet. These results indicate that NOS1b is a primary NOS1 isoformexpressed in themacula 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.

Original languageEnglish (US)
Pages (from-to)2346-2356
Number of pages11
JournalJournal of the American Society of Nephrology
Issue number8
StatePublished - 2016
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine


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