TY - JOUR
T1 - Macula densa NOS1b modulates renal hemodynamics and blood pressure during pregnancy
T2 - Role in gestational hypertension
AU - Wei, Jin
AU - Zhang, Jie
AU - Jiang, Shan
AU - Xu, Lan
AU - Qu, Larry
AU - Pang, Bo
AU - Jiang, Kun
AU - Wang, Lei
AU - Intapad, Suttira
AU - Buggs, Jacentha
AU - Cheng, Feng
AU - Mohapatra, Shyam
AU - Juncos, Luis A.
AU - Osborn, Jeffrey L.
AU - Granger, Joey P.
AU - Liu, Ruisheng
N1 - Publisher Copyright:
Copyright ß 2021 by the American Society of Nephrology
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
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U2 - 10.1681/ASN.2020070969
DO - 10.1681/ASN.2020070969
M3 - Article
C2 - 34127535
AN - SCOPUS:85116528350
SN - 1046-6673
VL - 32
SP - 2485
EP - 2500
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 10
ER -