{"doi":"10.1681/asn.2020070969","title":"Macula Densa NOS1β Modulates Renal Hemodynamics and Blood Pressure during Pregnancy: Role in Gestational Hypertension","abstract":"Significance Statement The mechanisms underlying the renal and systemic hemodynamic changes during normal pregnancy and gestational hypertension remain unclear. This study demonstrated that ( 1 ) in C57BL/6 mice, macula densa NOS1β was significantly upregulated in normal pregnancy but downregulated in a reduced uterine perfusion pressure (RUPP)–induced gestational hypertension model; ( 2 ) the normal pregnancy-induced renal hemodynamic changes were attenuated with a rise in blood pressure in macula densa–specific NOS1 knockout (MD-NOS1KO) mice; ( 3 ) the RUPP-induced hemodynamic alterations were diminished in MD-NOS1KO mice; and ( 4 ) in African green monkeys, renal cortical NOS1β expression was increased in normotensive pregnancies but decreased in gestational hypertensive pregnancies. These findings establish a critical role of macula densa NOS1β as a key determinant of, and therapeutic target for, gestational hypertension. Background Regulation of renal hemodynamics and BP via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the β-splice variant of nitric oxide synthase 1 (NOS1β) 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 NOS1β 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 NOS1β/NO levels, TGF responsiveness, GFR, and BP in wild-type and macula densa–specific NOS1 knockout (MD-NOS1KO) mice. Results Macula densa NOS1β 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 NOS1β, 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 NOS1β expression increased in normotensive pregnancies, but decreased in spontaneous gestational hypertensive pregnancies. Conclusions Macula densa NOS1β plays a critical role in the control of renal hemodynamics and BP during pregnancy.","journal":"Journal of the American Society of Nephrology","year":2021,"id":190065,"datarank":0.40620753016533157,"base_score":2.70805020110221,"endowment":2.70805020110221,"self_citation_contribution":0.40620753016533157,"citation_network_contribution":0.0,"self_endowment_contribution":0.40620753016533157,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":402931,"name":"Jie Zhang","orcid":"0000-0001-6717-4118","position":1,"is_corresponding":false},{"id":720284,"name":"Shan Jiang","orcid":"0000-0003-3763-1829","position":2,"is_corresponding":false},{"id":720286,"name":"Lan Xu","orcid":"0009-0009-9272-0040","position":3,"is_corresponding":false},{"id":754142,"name":"Larry Qu","orcid":null,"position":4,"is_corresponding":false},{"id":753552,"name":"Bo Pang","orcid":"0000-0001-6672-2346","position":5,"is_corresponding":false},{"id":720287,"name":"Kun Jiang","orcid":"0000-0003-4039-975X","position":6,"is_corresponding":false},{"id":753553,"name":"Lei Wang","orcid":"0009-0005-2757-1748","position":7,"is_corresponding":false},{"id":753554,"name":"Suttira Intapad","orcid":"0000-0003-0750-3252","position":8,"is_corresponding":false},{"id":720289,"name":"Jacentha Buggs","orcid":"0000-0002-2709-7530","position":9,"is_corresponding":false},{"id":422132,"name":"Feng Cheng","orcid":"0000-0003-3619-8090","position":10,"is_corresponding":false},{"id":553779,"name":"Shyam S. Mohapatra","orcid":"0000-0001-5838-0681","position":11,"is_corresponding":false},{"id":753555,"name":"Luis A. Juncos","orcid":"0000-0002-4630-2747","position":12,"is_corresponding":false},{"id":753556,"name":"Jeffrey L. Osborn","orcid":"0000-0002-2636-5345","position":13,"is_corresponding":false},{"id":411930,"name":"Joey P. 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