Macula densa NOS1b modulates renal hemodynamics and blood pressure during pregnancy: Role in gestational hypertension

Jin Wei, Jie Zhang, Shan Jiang, Lan Xu, Larry Qu, Bo Pang, Kun Jiang, Lei Wang, Suttira Intapad, Jacentha Buggs, Feng Cheng, Shyam Mohapatra, Luis A. Juncos, Jeffrey L. Osborn, Joey P. Granger, Ruisheng Liu

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background Regulation of renal hemodynamics and BP via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the b-splice variant of nitric oxide synthase 1 (NOS1b) in the macula densa is a primary modulator of TGF, we evaluated its role in normal pregnancy and gestational hypertension in a mouse model. We hypothesized that pregnancy upregulates NOS1b in the macula densa, thus blunting TGF, allowing the GFR to increase and BP to decrease. Methods We used sophisticated techniques, including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of renal tubules in vivo, clearance kinetics of plasma FITC-sinistrin, and radiotelemetry BP monitoring, to determine the effects of normal pregnancy or reduced uterine perfusion pressure (RUPP) on macula densa NOS1b/NO levels, TGF responsiveness, GFR, and BP in wild-type and macula densa–specific NOS1 knockout (MD-NOS1KO) mice. Results Macula densa NOS1b was upregulated during pregnancy, resulting in blunted TGF, increased GFR, and decreased BP. These pregnancy-induced changes in TGF and GFR were largely diminished, with a significant rise in BP, in MD-NOS1KO mice. In addition, RUPP resulted in a downregulation in macula densa NOS1b, enhanced TGF, decreased GFR, and hypertension. The superimposition of RUPP into MD-NOS1KO mice only caused a modest further alteration in TGF and its associated changes in GFR and BP. Finally, in African green monkeys, renal cortical NOS1b expression increased in normotensive pregnancies, but decreased in spontaneous gestational hypertensive pregnancies. Conclusions Macula densa NOS1b plays a critical role in the control of renal hemodynamics and BP during pregnancy.

Original languageEnglish
Pages (from-to)2485-2500
Number of pages16
JournalJournal of the American Society of Nephrology
Volume32
Issue number10
DOIs
StatePublished - Oct 2021

Bibliographical note

Funding Information:
causative role is supported by the finding that the MD-NOS1KO mice develop gestational hypertension. We further tested this possibility by determining whether superimposing RUPP in the MD-NOS1KO mice have an additive effect; the lack of an additive effect would support that they are working via the same mechanism. The two key points are that pregnancy-induced alterations in TGF, GFR, and BP, in MD-NOS1KO (non-RUPP) mice, were similar to RUPP (wild-type) mice. Although the superimposition of RUPP in the MD-NOS1KO mice worsened the parameters, it did so by a modest degree, suggesting they were at least partially working via the same mechanism. Definitive experiments would require rescuing of NOS1b in the macula densa. Although we are unable to perform these experiments, it is interesting to note that administering L-arginine to rats subjected to RUPP has been shown to attenuate the hypertension,54 further supporting the view that macula densa NOS1b is playing a causative role in gestational hypertension.

Publisher Copyright:
Copyright ß 2021 by the American Society of Nephrology

ASJC Scopus subject areas

  • Nephrology

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