Faculty Opinions recommendation of Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway.

Chronic kidney disease (CKD) causes salt-sensitive hypertension that is often resistant to treatment and contributes to the progression of kidney injury and cardiovascular disease. A better understanding of the mechanisms contributing to salt-sensitive hypertension in CKD is essential to improve these outcomes. This review critically explores these mechanisms by focusing on how CKD affects distal nephron Na+ reabsorption. CKD causes glomerulotubular imbalance with reduced proximal Na+ reabsorption and increased distal Na+ delivery and reabsorption. Aldosterone secretion further contributes to distal Na+ reabsorption in CKD and is not only mediated by renin and K+ but also by metabolic acidosis, endothelin-1, and vasopressin. CKD also activates the intrarenal renin-angiotensin system, generating intratubular angiotensin II to promote distal Na+ reabsorption. High dietary Na+ intake in CKD contributes to Na+ retention by aldosterone-independent activation of the mineralocorticoid receptor mediated through Rac1. High dietary Na+ also produces an inflammatory response mediated by T helper 17 cells and cytokines increasing distal Na+ transport. CKD is often accompanied by proteinuria, which contains plasmin capable of activating the epithelial Na+ channel. Thus, CKD causes both local and systemic changes that together promote distal nephron Na+ reabsorption and salt-sensitive hypertension. Future studies should address remaining knowledge gaps, including the relative contribution of each mechanism, the influence of sex, differences between stages and etiologies of CKD, and the clinical relevance of experimentally identified mechanisms. Several pathways offer opportunities for intervention, including with dietary Na+ reduction, distal diuretics, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and K+ or H+ binders.

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Abstract P235: The Additive Genetic Association of Beta-2 Adrenergic Receptor and Serum-and-Glucocorticoid-Inducible Kinase 1 on Salt-Sensitive Hypertension

Hypertension ◽

10.1161/hyp.76.suppl_1.p235 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Yan Emily Yuan ◽

Andrea V Haas ◽

Li En Yee ◽

Yinhan Wong ◽

Jonathan S Williams ◽

...

Keyword(s):

Adrenergic Receptor ◽

Multivariate Regression ◽

Mineralocorticoid Receptor ◽

Risk Allele ◽

Sodium Reabsorption ◽

Regression Analyses ◽

Mineralocorticoid Receptor Antagonist ◽

Beta 2 ◽

Salt Sensitive Hypertension ◽

Gene Association Study

Salt sensitivity of blood pressure (SSBP) is associated with increased cardiovascular morbidity. A diplotype on the beta 2 adrenergic receptor (β2AR) gene (rs1042713, rs1042714)—associated with increased aldosterone (ALDO)—and a polymorphism in the serum-and-glucocorticoid-inducible kinase 1 (SGK1) gene (rs2758151)—an ALDO target that increases sodium reabsorption—are each associated with SSBP. We hypothesized that SSBP will be increased in homozygotes for both β2AR and SGK1 (Combo) when compared to non-risk homozygotes and homozygotes in either gene alone. The HyperPATH database includes individuals who completed 7 days of both restricted and liberal sodium diets to determine systolic SSBP. We conducted a gene association study in 329 individuals: 42 were homozygotes for Combo; 242 were homozygotes for β2AR or SGK1; and 45 were non-carriers. Multivariate regression analyses (adjusted for age, sex, BMI, race, hypertension) found a significantly higher SSBP in the Combo homozygotes when compared to non-carriers and homozygotes for either β2AR or SGK1(p<0.001, 95% CI: 2.35, 7.56) (Figure 1). Serum ALDO levels were higher in Combo homozygotes than in the other groups (p=0.035, CI: 0.069,1.87). Additionally, analyses of either gene alone with SSBP (β2AR: p=0.056, CI: -0.038, 2.89; SGK1: p=0.003, CI: 0.87, 4.35) was less than what was observed in the Combo. In sum, Combo homozygotes for SGK1 and β2AR substantially increased the level of SSBP compared to that observed in risk allele homozygotes in each gene alone. Thus, hypertensive Combo homozygotes are likely candidates for mineralocorticoid receptor antagonist therapy—gene driven, personalized medicine. Figure 1.

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Abstract 11005: Activation of Hypothalamic Mineralocorticoid Receptor-Independent Epithelial Sodium Channels Leads to Salt-Sensitive Hypertension in Mouse Model of Metabolic Syndrome

Circulation ◽

10.1161/circ.132.suppl_3.11005 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Mutsumi Kunita-Takanezawa ◽

Koji Ito ◽

Takuya Kishi ◽

Yoshitaka Hirooka

Keyword(s):

Metabolic Syndrome ◽

Mineralocorticoid Receptor ◽

Tap Water ◽

Urinary Sodium Excretion ◽

Normal Diet ◽

Salt Loading ◽

Intracerebroventricular Infusion ◽

Induced Hypertension ◽

Plasma Arginine ◽

Salt Sensitive Hypertension

Introduction and Hypothesis: Metabolic syndrome (MetS) is often associated with salt-sensitive hypertension. In genetic salt-sensitive hypertensive models, activation of the hypothalamic mineralocorticoid receptor (MR)-epithelial sodium channel (ENaC) pathway has been established as a major worsening factor. However, in MetS, contribution of the hypothalamic MR-ENaC pathway to salt-sensitive hypertension remains unknown. Therefore, we determined whether the hypothalamic MR-ENaC pathway activation leads to salt-sensitive hypertension in MetS. Methods and Results: Diet-induced obesity (DIO) was achieved in male C57BL/6 mice by feeding them a high-fat diet from 4 weeks of age. Mice fed a normal diet served as controls (CON). Mice at 12 weeks of age were given tap water with regular salt (RS) or 1% NaCl (high salt; HS) for 8 weeks. HS led to increased systolic blood pressure only in DIO-mice, and not in CON-mice (DIO-HS: 122±3 mmHg vs DIO-RS: 107±2 mmHg, CON-HS: 109±2 mmHg vs CON-RS: 105±1 mmHg, n=6/group, p<0.05). In DIO-mice, 24-h urinary norepinephrine excretion after salt loading was significantly higher than that before salt loading (244±18 ng/day vs 371±29 ng/day, n=6 in each, p<0.05). HS-induced hypertension was significantly prevented by intracerebroventricular infusion of the ENaC blocker benzamil (Ben), but not the MR blocker spironolactone (Spl; DIO-HS-Vehicle 122±1 mmHg, DIO-HS-Ben 108±1 mmHg, DIO-HS-Spl 119±1 mmHg, n=6 in each, p<0.05). Expression of hypothalamic serum and glucocorticoid-regulated kinase (SGK) 1, a marker of MR activity, did not differ between in CON-mice and DIO-mice. However, the SGK1 phosphorylation level was greater in DIO-mice than in CON-mice, suggesting MR-independent SGK1 activation. Water intake and urinary sodium excretion did not differ between in DIO-HS-Vehicle and DIO-HS-Ben. Interestingly, salt loading-induced plasma arginine vasopressin (AVP) secretion was significantly prevented in DIO-HS-Ben. Conclusions: These findings suggest that salt-induced hypertension in DIO-mice results from MR-independent hypothalamic SGK1-ENaC activation with systemic AVP secretion. Hypothalamic ENaC could be a novel therapeutic target in salt-induced hypertension of MetS.

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