Inverse salt sensitivity: an independent risk factor for cardiovascular damage in essential hypertension

Çuka, Ermira; Simonini, Marco; Lanzani, Chiara; Zagato, Laura; Citterio, Lorena; Messaggio, Elisabetta; Faienza, Sipontina; Brioni, Elena; Hamlyn, John M.; Manunta, Paolo

doi:10.1097/hjh.0000000000003174

Cited by 6 publications

(7 citation statements)

References 45 publications

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“…As sodium load increases, endothelial function decreases, resulting in impaired vascular relaxation and elevated blood pressure. Diuretics are effective in lowering blood pressure caused by a high-salt diet, but their adverse effects, such as low potassium and high uric acid, also require attention in clinic (Cuka, Simonini, et al, 2022;Garfinkle, 2017).…”

Section: Discussionmentioning

confidence: 99%

Anti-hypertensive Effect of a Novel Angiotensin II Receptor Neprilysin Inhibitor (ARNi) -S086 in DSS rat model

Sun¹,

Yan²,

Xiao³

et al. 2023

Preprint

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Background and Purpose: Angiotensin receptor-NEP inhibitor (ARNi), which is consisting of an angiotensin receptor blocker (ARB) and a neprilysin inhibitor (NEPi), has been proven safe and effective for treating hypertension. S086 is a novel ARNi cocrystal developed by Salubris for the treatment of heart failure and hypertension. Rat hypertension model and telemetry system were used in our study to investigate circadian rhythm of rat blood pressure and evaluate the anti-hypertensive efficacy of S086. Experimental Approach: Dahl Salt Sensitive (DSS) hypertensive rat model and telemetry system were used in this research. Key Results: Our findings revealed the circadian rhythm of DSS rat blood pressure was opposite to that of humans, with high blood pressure occurring during the night. Oral administration of S086 dose-dependently lowered the blood pressure and exhibited better efficacy than LCZ696, particularly 16-24h after dosing. No significant changes were observed on water consumption, natriuresis and diuresis among all high salt groups. Conclusion: This paper demonstrates the ability of anti-hypertensive effect of S086 in preclinic and supports the product to conduct phase 2/3 clinical trial. Implications: This study reveals circadian rhythm of DSS rat blood pressure and provides the anti-hypertensive efficacy of S086 to support the further clinical study.

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Section: Discussionmentioning

confidence: 99%

Anti-hypertensive Effect of a Novel Angiotensin II Receptor Neprilysin Inhibitor (ARNi) -S086 in DSS rat model

Sun¹,

Yan²,

Xiao³

et al. 2023

Preprint

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“…However, about 11% of individuals have increased BP when the intake of salt is very low (<1.2–3 g/day) [ 23 , 24 , 25 , 47 , 84 , 85 ]. In one recent long-term study (median 16 years, IQR 12–17 years [ 26 ]) individuals with ISS had a 15-fold increase of end-organ damage and mortality compared with individuals with SR. Whereas several genes have been proposed to cause SS [ 4 , 36 , 37 , 38 , 39 , 40 , 41 , 43 , 45 ], little is known about genes that contribute to ISS.…”

Section: Discussionmentioning

confidence: 99%

“…Given that ISS and SS constitute ~33% of the US population and both are associated with increased morbidity and mortality [ 110 , 111 ] then there is a need for diagnostic markers for these conditions. Surrogate markers obtained from random urine specimens may be used in the future to determine each individual’s personal salt index [ 20 , 26 , 33 , 40 , 44 ] that might encourage dietary adjustments leading to improved population health.…”

Section: Discussionmentioning

confidence: 99%

“…Others have measured the consequences (e.g., cardiovascular disease and death) in individuals with ISS. Long-term clinical studies (median 16 years, IQR 12–17 years [ 26 , 27 ]) showed that individuals with the ISS phenotype had a 15-fold greater risk of target organ damage than individuals with the salt resistance (SR) phenotype, as determined by clinical evaluation of the heart, kidney, vasculature, and brain, as well as a history of cardiovascular events similar to those seen in salt-sensitive individuals [ 26 ]. Our studies are the first to examine the biological, genetic, and epigenetic mechanisms associated with the paradoxical increase in BP in adults consuming a low sodium diet [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Castiglioni used a low sodium (30 mmol NaCl per day) and a high-sodium (200 mmol NaCl per day) diet, each for 5 days, in random order in 71 Italian participants [ 32 ]. The authors of all four studies observed a population of study participants that experienced a change in BP that was opposite to that of individuals with SS [ 23 , 24 , 25 , 32 ], that others have shown to be associated with increased mortality and morbidity [ 17 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Inverse Salt Sensitivity of Blood Pressure Is Associated with an Increased Renin-Angiotensin System Activity

Gildea

Schiermeyer

et al. 2022

Biomedicines

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High and low sodium diets are associated with increased blood pressure and cardiovascular morbidity and mortality. The paradoxical response of elevated BP in low salt diets, aka inverse salt sensitivity (ISS), is an understudied vulnerable 11% of the adult population with yet undiscovered etiology. A linear relationship between the number of single nucleotide polymorphisms (SNPs) in the dopamine D2 receptor (DRD2, rs6276 and 6277), and the sodium myo-inositol cotransporter 2 (SLC5A11, rs11074656), as well as decreased expression of these two genes in urine-derived renal proximal tubule cells (uRPTCs) isolated from clinical study participants suggest involvement of these cells in ISS. Insight into this newly discovered paradoxical response to sodium is found by incubating cells in low sodium (LS) conditions that unveil cell physiologic differences that are then reversed by mir-485-5p miRNA blocker transfection and bypassing the genetic defect by DRD2 re-expression. The renin-angiotensin system (RAS) is an important counter-regulatory mechanism to prevent hyponatremia under LS conditions. Oversensitive RAS under LS conditions could partially explain the increased mortality in ISS. Angiotensin-II (AngII, 10 nmol/L) increased sodium transport in uRPTCs to a greater extent in individuals with ISS than SR. Downstream signaling of AngII is verified by identifying lowered expression of nuclear factor erythroid 2-related factor 2 (NRF2), CCCTC-binding factor (CTCF), and manganese-dependent mitochondrial superoxide dismutase (SOD2) only in ISS-derived uRPTCs and not SR-derived uRPTCs when incubated in LS conditions. We conclude that DRD2 and SLC5A11 variants in ISS may cause an increased low sodium sensitivity to AngII and renal sodium reabsorption which can contribute to inverse salt-sensitive hypertension.

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A novel mouse model recapitulates the effects of rs2254524 variant in the lanosterol synthase gene on salt sensitivity and organ damage

Faienza,

Citterio,

Messaggio

et al. 2024

Journal of Hypertension

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Objective: The blood pressure (BP) response to salt intake (salt sensitivity) shows great variability among individuals and is more frequent in hypertensive patients. Elevated levels of the steroid hormone Endogenous Ouabain (EO) are associated with hypertension (HT) and salt sensitivity. The lanosterol synthase gene (LSS) plays a key role in the biosynthesis of steroids and its rs2254524 variant (Val642Leu) is linked to salt sensitivity in humans. This study aims to investigate the pathophysiological significance of the Lss missense variation in a new knock-in mouse model of salt-sensitive HT onset. Methods: We generated a mouse model carrying the murine homolog (Val643Leu) of the human LSS variant. C57BL/6N Lss V643L/V643L mice were fed different NaCl diets (low-salt, LSD; normal-salt, NSD; high-salt, HSD) and were characterized at functional, histological, and molecular levels. Results: At baseline, mutant mice showed an enlarged kidney compared to the wild-type (WT) counterpart, but the Lss V643L variant did not affect EO biosynthesis nor systolic BP at 3 and 12 months. In HSD, we observed an increased systolic BP only in 12-month-old Lss V643L/V643L mice, compared to NSD. Moreover, only the HSD Lss V643L/V643L mice showed cardiac hypertrophy and a higher incidence of cardiac fibrosis compared to WT at 12 months. Finally, the Lss mRNA level was differentially regulated by HSD in the adrenal gland, liver, and heart of Lss V643L/V643L mice compared to WT. Conclusions: The novel Lss mouse model resembles the salt-sensitive HT phenotype observed in hypertensive patients and provides a good model of salt-sensitive HT and HT-mediated organ damage.

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Inverse salt sensitivity: an independent risk factor for cardiovascular damage in essential hypertension

Cited by 6 publications

References 45 publications

Anti-hypertensive Effect of a Novel Angiotensin II Receptor Neprilysin Inhibitor (ARNi) -S086 in DSS rat model

Anti-hypertensive Effect of a Novel Angiotensin II Receptor Neprilysin Inhibitor (ARNi) -S086 in DSS rat model

Inverse Salt Sensitivity of Blood Pressure Is Associated with an Increased Renin-Angiotensin System Activity

A novel mouse model recapitulates the effects of rs2254524 variant in the lanosterol synthase gene on salt sensitivity and organ damage

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