Jin Wei1, Jie Zhang2, Shan Jiang2, Lan Xu3, Larry Qu2, Bo Pang4, Kun Jiang5, Lei Wang2, Suttira Intapad6, Jacentha Buggs7, Feng Cheng8, Shyam Mohapatra8, Luis A Juncos4, Jeffrey L Osborn9, Joey P Granger10, Ruisheng Liu2. 1. Department of Molecular Pharmacology & Physiology, University of South Florida, Tampa, Florida jwei@usf.edu. 2. Department of Molecular Pharmacology & Physiology, University of South Florida, Tampa, Florida. 3. College of Public Health, University of South Florida, Tampa, Florida. 4. Department of Internal Medicine, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. 5. Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 6. Department of Pharmacology, School of Medicine, Tulane University, New Orleans, Louisiana. 7. Advanced Organ Disease & Transplantation Institute, Tampa, Florida. 8. Department of Pharmaceutical Science, University of South Florida, Tampa, Florida. 9. Department of Biology, University of Kentucky, Lexington, Kentucky. 10. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
Abstract
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.
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.
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