Journal article
Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension
Cardiovascular research, Vol.117(1), pp.308-319
05/19/2020
DOI: 10.1093/cvr/cvaa147
PMID: 32428209
Abstract
Abstract Aims Salt-sensitive (SS) hypertension is accompanied by impaired vasodilation in the systemic and renal circulation. However, the causal relationship between vascular dysfunction and salt-induced hypertension remains controversial. We sought to determine whether primary vascular dysfunction, characterized by a failure to vasodilate during salt loading, plays a causal role in the pathogenesis of SS hypertension. Methods and results Mice selectively expressing a peroxisome proliferator-activated receptor γ dominant-negative mutation in vascular smooth muscle (S-P467L) exhibited progressive SS hypertension during a 4 week high salt diet (HSD). This was associated with severely impaired vasodilation in systemic and renal vessels. Salt-induced impairment of vasodilation occurred as early as 3 days after HSD, which preceded the onset of SS hypertension. Notably, the overt salt-induced hypertension in S-P467L mice was not driven by higher cardiac output, implying elevations in peripheral vascular resistance. In keeping with this, HSD-fed S-P467L mice exhibited decreased smooth muscle responsiveness to nitric oxide (NO) in systemic vessels. HSD-fed S-P467L mice also exhibited elevated albuminuria and a blunted increase in urinary NO metabolites which was associated with blunted renal blood flow and increased sodium retention mediated by a lack of HSD-induced suppression of NKCC2. Blocking NKCC2 function prevented the salt-induced increase in blood pressure in S-P467L mice. Conclusion We conclude that failure to vasodilate in response to salt loading causes SS hypertension by restricting renal perfusion and reducing renal NO through a mechanism involving NKCC2 in a mouse model of vascular peroxisome proliferator-activated receptor γ impairment.
Details
- Title: Subtitle
- Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension
- Creators
- Jing Wu - Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA, Department of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Rd., 2-248 BSB, Iowa City, IA 52242, USALarry N Agbor - Department of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Rd., 2-248 BSB, Iowa City, IA 52242, USAShi Fang - Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA, Department of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Rd., 2-248 BSB, Iowa City, IA 52242, USAMasashi Mukohda - Department of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Rd., 2-248 BSB, Iowa City, IA 52242, USAAnand R Nair - Department of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Rd., 2-248 BSB, Iowa City, IA 52242, USAPablo Nakagawa - Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA, Department of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Rd., 2-248 BSB, Iowa City, IA 52242, USAAvika Sharma - Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, L334, Portland, OR 97239, USADonald A Morgan - Department of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Rd., 2-248 BSB, Iowa City, IA 52242, USAJustin L Grobe - Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA, Department of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Rd., 2-248 BSB, Iowa City, IA 52242, USAKamal Rahmouni - Department of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Rd., 2-248 BSB, Iowa City, IA 52242, USA, Veteran Affairs Health Care System, 601 Hwy 6 West, Iowa City, IA 52242, USA, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Rd., 2-248 BSB, Iowa City, IA 52242, USARobert M Weiss - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Rd., 2-248 BSB, Iowa City, IA 52242, USAJames A McCormick - Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, L334, Portland, OR 97239, USACurt D Sigmund - Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA, Department of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Rd., 2-248 BSB, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Cardiovascular research, Vol.117(1), pp.308-319
- DOI
- 10.1093/cvr/cvaa147
- PMID
- 32428209
- NLM abbreviation
- Cardiovasc Res
- ISSN
- 0008-6363
- eISSN
- 1755-3245
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health; DOI: 10.13039/100000002, name: NIH, award: HL084207, HL144807, HL134850, DK098141, DK117903; DOI: 10.13039/100000968, name: American Heart Association, award: 15SFRN23480000, 18EIA33890055; name: Cardiac Imaging Core at the University of Iowa; DOI: 10.13039/100000002, name: NIH, award: OD019941, 17POST33660685; name: Cardiovascular Interdisciplinary Research Fellowship, award: T32HL007121; name: Iowa Cardiovascular Interdisciplinary Research Fellowship, award: T32HL007121; name: Iowa Training Program in Kidney and Hypertension Research, award: T32DK007690; name: MCW Training in Signature Transdisciplinary Cardiovascular Sciences, award: T32HL134643; DOI: 10.13039/100000002, name: NIH, award: HL084207; DOI: 10.13039/100000738, name: Department of Veterans Affairs, award: BX004249; name: University of Iowa Fraternal Order of Eagles Diabetes Research Center
- Language
- English
- Date published
- 05/19/2020
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984070479302771
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