Mechanism of Salt-Sensitive Hypertension: Focus on Adrenal and Sympathetic Nervous Systems
Open accessAbstract
A central role for the kidney among the systems contributing to BP regulation and the development of hypertension has been proposed. Both the aldosterone/mineralocorticoid receptor pathway and the renal sympathetic nervous system have important roles in the regulation of renal excretory function and BP control, but the mechanisms underlying these processes have remained unclear. However, recent studies revealed the activation of two pathways in salt-sensitive hypertension. Notably, Rac1, a member of the Rho-family of small GTP binding proteins, was identified as a novel ligand-independent modulator of mineralocorticoid receptor activity. Furthermore, these studies point to crucial roles for the Rac1-mineralocorticoid receptor-NCC/ENaC and the renal β-adrenergic stimulant-glucocorticoid receptor-WNK4-NCC pathways in certain rodent models of salt-sensitive hypertension. The nuclear mineralocorticoid and glucocorticoid receptors may contribute to impaired renal excretory function and the resulting salt-sensitive hypertension by increasing sodium reabsorption at different tubular segments. This review provides an in-depth discussion of the evidence supporting these conclusions and considers the significance with regard to treating salt-sensitive hypertension and salt-induced cardiorenal injury.
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Rac1 stimulates mineralocorticoid receptor signalling, and Rac1 levels in renal epithelial cells are increased in obese rodents.
“Racl stimulates MR signalling, and the levels of Racl in renal epithelial cells were increased in obese rodents.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [82]
Rac1 inhibitors ameliorated proteinuria and kidney injury in obese rodents and in rodents with salt-sensitive hypertension.
“In addition, Racl inhibitors amelio-rated proteinuria and kidney injury in obese rodents and in rodents with salt-sensitive hypertension82.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [82]
Obesity causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II.
“However, obesity also causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II.”
From Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms (2015) · cites this paper as [54]
BP reductions after MR antagonism in obese patients with resistant hypertension occurred despite concurrent therapy with ACE inhibitors or ARBs, suggesting that MR activation in obesity can occur independently of AngII-mediated stimulation of aldosterone secretion.
“BP reductions after MR antagonism in obese patients with resistant hypertension occurred despite concurrent therapy with ACE inhibitors or ARBs, suggesting that MR activation in obesity can occur independently of AngII-mediated stimulation of aldosterone secretion54.”
From Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms (2015) · cites this paper as [54]
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Xiao, B., Liu, F., Lu, J., Chen, F., Pei, W., & Yang, X. (2019) · Physiological Research · doi:10.33549/physiolres.933918 · Cited by 4 · see citing works
Cao, Z., Wang, J., Pang, N., Lin, Y., & Liu, X. (2025) · Cardiovascular Diabetology – Endocrinology Reports · doi:10.1186/s40842-025-00255-3 · Cited by 3 · see citing works
Choi, H., Jung, I. M., & Kim, S. W. (2025) · Antioxidants · doi:10.3390/antiox14010100 · Cited by 3 · see citing works
Unraveling the Potential of SGK1 in Osteoporosis: From Molecular Mechanisms to Therapeutic Targets
Yang, F., Chen, C., Chen, R., Yang, C., Liu, Z., Wen, L., Xiao, H., Geng, B., & Xia, Y. (2025) · Biomolecules · doi:10.3390/biom15050686 · Cited by 3 · see citing works
A Succinct Analysis of Hypertension and its Management Strategies
Gupta, P., & Parashar, A. K. (2023) · International Journal of Newgen Research in Pharmacy & Healthcare · doi:10.61554/ijnrph.v1i1.2023.24 · Cited by 3 · see citing works
Physiology of the Developing Kidney: Sodium and Water Homeostasis and Its Disorders
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Rajab, S. K., & Bakuza, S. S. (2024) · East African Health Research Journal · doi:10.24248/eahrj.v8i1 · Cited by 3 · see citing works
Dynamic changes in renal sodium handling during sympathetic stimulation in healthy human males
Petersen, J. C. G., Jonassen, T. E. N., Holstein‐Rathlou, N., Petersen, L. G., & Sørensen, C. M. (2023) · Autonomic Neuroscience · doi:10.1016/j.autneu.2023.103131 · Cited by 2 · see citing works
Sex Differences in the Central Control of Sodium Appetite and Blood Pressure
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- Authors
- Fujita, T.
- Affiliations
- Research Center for Advanced Science and Technology, The University of Tokyo (JP)
- Corresponding author
- Fujita, Toshiro
- ORCID
- Fujita, Toshiro
- Venue
- Journal of the American Society of Nephrology
- Published
- 2014-06
- Volume
- 25
- Issue
- 6
- Pages
- 1148-1155
- ISSN
- 1046-6673 (ISSN-L)
- PMC
- PMC4033384
- OpenAlex
- W2157066558
- Cited by
- 124
- References
- 89
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 8 · 2023: 11 · 2022: 12 · 2021: 7 · 2020: 12 · 2019: 16 · 2018: 11 · 2017: 15 · 2016: 6 · 2015: 10 · 2014: 3 · 2013: 1
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of the American Society of Nephrology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (26670426, 24659410, 21229012)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- salt-sensitive hypertension, mineralocorticoid receptor, glucocorticoid receptor, Rac1, WNK4, sodium chloride cotransporter, epithelial sodium channel, renal sodium reabsorption, renal excretory function, renal sympathetic nervous system, aldosterone, Rho GTPases, blood pressure regulation
- MeSH terms
- Animals, Blood Pressure, Humans, Hypertension, Renal, Kidney, Sympathetic Nervous System, Sodium Chloride, Dietary
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