scholarly journals Renocardiac protective effects of SGLT2 inhibitor combined with angiotensin receptor blocker in salt sensitive Dahl rats

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
H Ito ◽  
K Dohi ◽  
Y Zhe ◽  
Y Ali ◽  
K Katayama ◽  
...  
Keyword(s):  
Combination Treatment ◽  
Sglt2 Inhibitor ◽  
Salt Sensitivity ◽  
High Salt ◽  
Protein Expression Level ◽  
High Salt Diet ◽  
Salt Diet ◽  
Sodium Transporters ◽  
Cont Group ◽  
Pressure Natriuresis

Abstract Background Kidney plays a central role in regulating salt-sensitivity of blood pressure (BP) to governs sodium excretion via several mechanisms including pressure natriuresis and the actions of renal sodium transporters. Purpose We clarified the effects of combination treatment of sodium-glucose cotransporter 2 (SGLT2) inhibitor and angiotensin receptor blocker (ARB) on BP and the pathogenesis of renocardiac injuries, and elucidated underlying molecular mechanisms involved in the regulation of renal sodium handling in the development of salt-sensitivity by comparing with each monotreatment in Dahl salt-sensitive (DSS) hypertensive rats. Methods DSS rats were treated orally for 8-weeks with normal salt diet (0.3% NaCl) (NS/Cont group), high salt diet (8% NaCl) (HS/Cont group), high salt diet with ipragliflozin (0.04%) (HS/Ipra group), high salt diet with losartan (0.05%) (HS/Los group), or high salt diet with combination of ipragliflozin and losartan (HS/Ipra+Los group). Results The combination group significantly reduced systolic BP compared with either high salt diet control group, losartan or ipragliflozin monotreatment groups (HS/Ipra+Los: 182.5±18.4mmHg vs HS/Cont: 227.7±26.1; HS/Ipra: 216.6±26.9; HS/Los: 208.6±21.6, at 8-weeks of treatment, P<0.05, respectively) (Figure 1A). The slope of pressure-natriuresis curve was significantly increased in the HS/Ipra+Los group compared to that in the HS/Cont group (interaction P=0.024), HS/Ipra group (P=0.009), and HS/Los group (P=0.084) using the linear regression model (Figure 1B), which indicated that only the combination treatment of ipragliflozin and losartan improved salt-sensitivity. The combined treatment significantly improved creatinine clearance (HS/Ipra+Los: 3.3±0.9mL/min vs HS/Cont: 1.1±0.5; HS/Ipra: 1.7±0.6; HS/Los: 1.9±0.8, P<0.05, respectively). The combination treatment also significantly ameliorated glomerulosclerosis, and improved cardiomyocyte hypertrophy and perivascular fibrosis (Figure 1C). Angiotensin II type 1 receptor (AT1R) protein expression level in the kidney was remarkably suppressed in the combination treatment group compared to the other high salt diet groups. The protein expression level of Na+/H+ exchanger isoform 3 (NHE3) and Na+-K+-Cl– cotransporter 2 (NKCC2), two of major sodium transports in the renal tubules, were significantly decreased with losartan monotreatment and combination treatment, but not with ipragliflozin monotreatment (Figure 2). Conclusions The dual inhibition of SGLT2 and AT1R effectively improved salt-sensitivity via reducing renal expression levels of the sodium transporters, which eventually lead to renocardiac protection. Thus, the combination treatment could be a novel and useful therapeutic strategy for treating salt-sensitive hypertension and renal injury in non-diabetic patients. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Scientific Research

scholarly journals Activation of the Sympathetic Nervous System Promotes Blood Pressure Salt-Sensitivity in C57BL6/J Mice

Hypertension ◽  
2021 ◽  
Vol 77 (1) ◽  
pp. 158-168
Author(s):  
Ailsa F. Ralph ◽  
Celine Grenier ◽  
Hannah M. Costello ◽  
Kevin Stewart ◽  
Jessica R. Ivy ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Salt Intake ◽  
Salt Sensitivity ◽  
High Salt ◽  
Sodium Balance ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Pressure Natriuresis

Global salt intake averages >8 g/person per day, over twice the limit advocated by the American Heart Association. Dietary salt excess leads to hypertension, and this partly mediates its poor health outcomes. In ≈30% of people, the hypertensive response to salt is exaggerated. This salt-sensitivity increases cardiovascular risk. Mechanistic cardiovascular research relies heavily on rodent models and the C57BL6/J mouse is the most widely used reference strain. We examined the effects of high salt intake on blood pressure, renal, and vascular function in the most commonly used and commercially available C57BL6/J mouse strain. Changing from control (0.3% Na + ) to high salt (3% Na + ) diet increased systolic blood pressure in male mice by ≈10 mm Hg within 4 days of dietary switch. This hypertensive response was maintained over the 3-week study period. Returning to control diet gradually reduced blood pressure back to baseline. High-salt diet caused a rapid and sustained downregulation in mRNA encoding renal NHE3 (sodium-hydrogen-exchanger 3) and EnaC (epithelial sodium channel), although we did not observe a suppression in aldosterone until ≈7 days. During the development of salt-sensitivity, the acute pressure natriuresis relationship was augmented and neutral sodium balance was maintained throughout. High-salt diet increased ex vivo sensitivity of the renal artery to phenylephrine and increased urinary excretion of adrenaline, but not noradrenaline. The acute blood pressure–depressor effect of hexamethonium, a ganglionic blocker, was enhanced by high salt. Salt-sensitivity in commercially sourced C57BL6/J mice is attributable to sympathetic overactivity, increased adrenaline, and enhanced vascular sensitivity to alpha-adrenoreceptor activation and not sodium retention or attenuation of the acute pressure natriuresis response.

scholarly journals Renal denervation attenuates hypertension but not salt sensitivity in ETB receptor-deficient rats

2017 ◽  
Vol 313 (4) ◽  
pp. R425-R437 ◽  
Author(s):  
Bryan K. Becker ◽  
Amanda C. Feagans ◽  
Daian Chen ◽  
Malgorzata Kasztan ◽  
Chunhua Jin ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Low Frequency ◽  
Sympathetic Nerves ◽  
Salt Sensitivity ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Etb Receptor ◽  
Renal Sympathetic

Hypertension is a prevalent pathology that increases risk for numerous cardiovascular diseases. Because the etiology of hypertension varies across patients, specific and effective therapeutic approaches are needed. The role of renal sympathetic nerves is established in numerous forms of hypertension, but their contribution to salt sensitivity and interaction with factors such as endothelin-1 are poorly understood. Rats deficient of functional ETB receptors (ETB-def) on all tissues except sympathetic nerves are hypertensive and exhibit salt-sensitive increases in blood pressure. We hypothesized that renal sympathetic nerves contribute to hypertension and salt sensitivity in ETB-def rats. The hypothesis was tested through bilateral renal sympathetic nerve denervation and measuring blood pressure during normal salt (0.49% NaCl) and high-salt (4.0% NaCl) diets. Denervation reduced mean arterial pressure in ETB-def rats compared with sham-operated controls by 12 ± 3 (SE) mmHg; however, denervation did not affect the increase in blood pressure after 2 wk of high-salt diet (+19 ± 3 vs. +16 ± 3 mmHg relative to normal salt diet; denervated vs. sham, respectively). Denervation reduced cardiac sympathetic-to-parasympathetic tone [low frequency-high frequency (LF/HF)] during normal salt diet and vasomotor LF/HF tone during high-salt diet in ETB-def rats. We conclude that the renal sympathetic nerves contribute to the hypertension but not to salt sensitivity of ETB-def rats.

Pressure natriuresis and cortical and papillary blood flow in inbred Dahl rats

1991 ◽  
Vol 261 (3) ◽  
pp. R595-R602 ◽  
Author(s):  
R. J. Roman ◽  
M. Kaldunski
Keyword(s):  
Blood Flow ◽  
Renal Perfusion ◽  
High Salt ◽  
Plasma Norepinephrine ◽  
High Salt Diet ◽  
Doppler Flowmetry ◽  
Salt Diet ◽  
Blood Flows ◽  
Low Salt ◽  
Pressure Natriuresis

The present study examined whether alterations in papillary blood flow, renal interstitial pressure (RIHP), and the pressure-natriuretic (PN) response are associated with the development of hypertension in inbred Dahl salt-sensitive (Dahl-S) rats. The PN responses were compared in 18- to 20-wk-old, Inactin-anesthetized, inbred Dahl salt-sensitive (S/Jr) and salt-resistant (R/Jr) rats fed a low-(0.3%) and a high- (8.0%) sodium chloride diet. Cortical and papillary blood flows were measured using laser-Doppler flowmetry. Neural and hormonal influences on the kidney were controlled by renal denervation and by fixing plasma norepinephrine, vasopressin, corticosterone, and aldosterone levels by intravenous infusion. The slope of the PN relationship in S/Jr rats maintained on a low-salt diet was 62% lower than that observed in R/Jr rats; however, whole kidney, cortical, and papillary blood flows and RIHP were not significantly different at any perfusion pressure studied. Glomerular filtration rate (GFR) was 25% lower in S/Jr rats than in R/Jr animals maintained on a low-salt diet. The slopes of the PN responses were similar in S/Jr and R/Jr rats exposed to a high-salt diet, but the entire relationship was shifted toward higher pressures by 20 mmHg in the S/Jr rats. Control cortical and papillary blood flows measured at control mean arterial pressures of 126 +/- 3 and 167 +/- 5 mmHg in R/Jr and S/Jr rats, respectively, were not significantly different. However, cortical and papillary blood flows were 25% lower in the S/Jr than in the R/Jr rats exposed to a high-salt diet when compared at equivalent renal perfusion pressures.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract 123: A Fructose-enriched Diet Stimulates Superoxide Production in Juxtaglomerular Cells and Prevents High-salt Induced Inhibition of Plasma Renin Activity (PRA)

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Mariela Mendez ◽  
Kevin L Gordish ◽  
Emily Henson ◽  
Pablo A Ortiz ◽  
William H Beierwaltes
Keyword(s):  
Plasma Renin Activity ◽  
Plasma Renin ◽  
Salt Sensitivity ◽  
High Salt ◽  
Superoxide Production ◽  
Renin Activity ◽  
Renin Release ◽  
High Salt Diet ◽  
Salt Diet ◽  
Salt Sensitive Hypertension

A fructose-enriched diet has been associated with hypertension. Western diets are rich in fructose and salt. We found that a fructose enriched diet plus high-salt induced salt sensitive hypertension. Plasma renin activity (PRA) is essential for blood pressure (BP) control. A high-salt diet decreases PRA by inhibiting renin release from juxtaglomerular (JG) cells. However it is not known if dietary fructose might impair the inhibition of renin release by high salt to promote salt sensitivity. Salt sensitive rats have enhanced levels of superoxide in the renal cortex, and we found that superoxide stimulates renin release from JG cells. Thus, we hypothesized that a fructose-enriched diet (20%) promotes salt sensitive hypertension in part by preventing high salt-induced inhibition of renin release from JG cells by enhancing superoxide production. To test this, Sprague Dawley rats were given 20% fructose in their drinking water, with normal or high salt diet (4% NaCl) for up to 4 weeks. Feeding normal rats a fructose+High-salt diet increased systolic BP by 30 mmHg whereas fructose or high-salt alone did not change BP (High-salt = 125±4, Fruct = 131±4, Fruct+High-salt = 147±7; n=6, p <0.05). A high-salt diet alone for 4 weeks decreased PRA by 85%. However, in rats fed fructose+High-salt did not decrease PRA (in ng AII/ml/hr: Ctrl = 2.51±0.72, High-salt = 0.43±0.07, Fruct = 2.71±0.9, Fruct+High-salt = 1.89±0.43; n=10, p <0.05). We next examined the role of the fructose or fructose+High-salt diet on NADPH oxidase expression in isolated JG cells. NOX4 expression was enhanced in JG cells from rats fed fructose+High-salt diet (n=4; p <0.05). Next, we measured superoxide production with Dihydroethidium and found it was higher in JG cells from rats fed fructose+high-salt diet compared to high-salt alone (% of Ctrl: High-salt = 90.7±37; fruct+High-salt = 289±85; n=4; p <0.05). We conclude that a 20% fructose-diet promotes salt sensitivity of BP. The mechanism may involve enhanced NOX4 expression and elevated superoxide levels within JG cells stimulating renin release. 15 million Americans consume 20% of their calories from fructose, and most, 4-8 times the recommended salt intake. Decreasing fructose intake could have a beneficial BP effect in hypertensive patients.

Renal Inflammation Induces Salt Sensitivity in Male db/db Mice through Dysregulation of ENaC

2021 ◽  
pp. ASN.2020081112
Author(s):  
Luciana C. Veiras ◽  
Justin Z. Y. Shen ◽  
Ellen A. Bernstein ◽  
Giovanna C. Regis ◽  
DuoYao Cao ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Salt Sensitivity ◽  
High Salt ◽  
Sodium Reabsorption ◽  
High Salt Diet ◽  
Salt Diet ◽  
Diabetic Kidney ◽  
Salt Sensitive Hypertension

BackgroundHypertension is considered a major risk factor for the progression of diabetic kidney disease. Type 2 diabetes is associated with increased renal sodium reabsorption and salt-sensitive hypertension. Clinical studies show that men have higher risk than premenopausal women for the development of diabetic kidney disease. However, the renal mechanisms that predispose to salt sensitivity during diabetes and whether sexual dimorphism is associated with these mechanisms remains unknown.MethodsFemale and male db/db mice exposed to a high-salt diet were used to analyze the progression of diabetic kidney disease and the development of hypertension.ResultsMale, 34-week-old, db/db mice display hypertension when exposed to a 4-week high-salt treatment, whereas equivalently treated female db/db mice remain normotensive. Salt-sensitive hypertension in male mice was associated with no suppression of the epithelial sodium channel (ENaC) in response to a high-salt diet, despite downregulation of several components of the intrarenal renin-angiotensin system. Male db/db mice show higher levels of proinflammatory cytokines and more immune-cell infiltration in the kidney than do female db/db mice. Blocking inflammation, with either mycophenolate mofetil or by reducing IL-6 levels with a neutralizing anti–IL-6 antibody, prevented the development of salt sensitivity in male db/db mice.ConclusionsThe inflammatory response observed in male, but not in female, db/db mice induces salt-sensitive hypertension by impairing ENaC downregulation in response to high salt. These data provide a mechanistic explanation for the sexual dimorphism associated with the development of diabetic kidney disease and salt sensitivity.

Abstract MP70: Aldosterone And Inverse Salt Sensitivity Of Blood Pressure

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Peng Xu ◽  
John J Gildea ◽  
Mahabuba Akhter ◽  
Robert M Carey ◽  
Wei Yue ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Salt Intake ◽  
Salt Sensitivity ◽  
High Salt ◽  
Sodium Reabsorption ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Low Salt ◽  
Harmful Effects

Salt sensitivity affects approximately 20% of adults worldwide and has similar mortality and morbidity sequalae as hypertension. Research has focused on the harmful effects of a high salt diet but have not focused on the harmful effects of a low salt diet. Inverse salt sensitive (ISS) individuals require high salt intake in order to maintain a normal blood pressure. Aldosterone increases ENaC and sodium reabsorption via the mineralocorticoid receptor (MR). We previously reported that αENaC was significantly lower in ISS renal tubule cells isolated from urine (uRTC), while these cells showed higher ENaC like activities under trypsin stimulation. We hypothesized that aldosterone may act as a stimulus and play a role in ISS high blood pressure on a low salt diet (LSD). Plasma aldosterone was significantly increased on LSD in all salt study participants, and ISS individuals showed the highest aldosterone level (ISS HS 3.8±0.38, n=26; ISS LS 35±3.38, n=22; SR HS 4.34±0.18, n=180; SR LS 32.62±1.6, n=152; SS HS 4.65±0.35, n=43; SS LS 26.08±2.18, n=38; HS Vs LS, p<0.001, two-way ANOVA). Moreover, both aldosterone and plasma renin activity (PRA) were significantly lower in salt sensitive (SS) individuals on LSD (PRA LS: ISS 6.05±0.87, n=17; SR 5.94±0.36, n=108; SS 4.43±0.57, n=34; p<0.05, one-way ANOVA), indicating LSD was protective to SS individuals. Treatment of uRTCs with 1 μM aldosterone increased MR and αENaC expression in ISS but not in SR (salt resistant) cells (MR: SR VEH 12164±213; SR Aldosterone 12327±128; ISS VEH 12128±40 vs ISS Aldosterone 13506±128, n=3, p<0.001, two-way ANOVA; αENaC: SR VEH 5023±46; SR Aldosterone 4895±55; ISS VEH 4270±21 vs ISS Aldosterone 5013±113, n=3, p<0.001, two-way ANOVA). High salt treatment further decreased MR in ISS but not in SR cells (ISS: 142mM 11066±188 vs 192mM 10425±74; p<0.05, n=3 two-way ANOVA). These results are consistent with the hypothesis that ISS individuals retain excess Na + and exhibit decreased BP when compared to SR or SS individuals under high salt diet, but reabsorb more sodium and exhibit elevated blood pressure under low salt diet. Higher circulating aldosterone and ex-vivo urine derived renal cell aldosterone sensitivity under low salt conditions may be a novel diagnostic test to identify ISS individuals.

463-P: Deterioration of Atherosclerosis via Dysbiosis in ApoE Null Mice Fed with High-Salt Diet

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 463-P
Author(s):  
TOMONORI KIMURA ◽  
YOSHITAKA HASHIMOTO ◽  
TAKAFUMI SENMARU ◽  
EMI USHIGOME ◽  
MASAHIDE HAMAGUCHI ◽  
...  
Keyword(s):  
High Salt ◽  
High Salt Diet ◽  
Salt Diet
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