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Evidence for Prohypertensive, Proinflammatory Effect of Interleukin-10 During Chronic High Salt Intake in the Condition of Elevated Angiotensin II Level.

ABSTRACT: IL-10 (interleukin-10) has been suggested to play a protective role in angiotensin II (AngII)-induced cardiovascular disorders. This study examined the role of endogenous IL-10 in salt-sensitive hypertension and renal injury induced by AngII. Responses to chronic AngII (400 ng/min per kilogram body weight; osmotic minipump) infusion were evaluated in IL-10 gene knockout mice fed with either normal salt diet (0.3% NaCl) or high salt (HS; 4% NaCl) diet, and these responses were compared with those in wild-type mice. Normal salt diets or HS diets were given alone for the first 2 weeks and then with AngII treatment for an additional 2 weeks (n=6 in each group). Arterial pressure was continuously monitored by implanted radio-telemetry, and a 24-hour urine collection was performed by metabolic cages on the last day of the experimental period. Basal mean arterial pressure was lower in IL-10 gene knockout mice than in wild-type (98±3 versus 113±3 mm Hg) mice. Mean arterial pressure responses to normal salt/HS alone or to the AngII+normal salt treatment were similar in both strains. However, the increase in mean arterial pressure induced by the AngII+HS treatment was significantly lower in IL-10 gene knockout mice (15±5% versus 37±3%) compared with wild-type mice. Renal tissue endothelial nitric oxide synthase expression (?3-folds) and urinary excretion of nitric oxide metabolites, nitrate/nitrite (1.2±0.1 versus 0.2±0.02 µmol/L/24 hours) were higher in IL-10 gene knockout mice compared with wild-type mice. These results indicate that an increase in nitric oxide production helps to mitigate salt-sensitive hypertension induced by AngII and suggest that a compensatory interaction between IL-10 and nitric oxide exists in modulating AngII-induced responses during HS intake.

SUBMITTER: Singh P

PROVIDER: S-EPMC5657538 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Evidence for Prohypertensive, Proinflammatory Effect of Interleukin-10 During Chronic High Salt Intake in the Condition of Elevated Angiotensin II Level.

Singh Purnima P Castillo Alexander A Islam M Toriqul MT Majid Dewan S A DSA

Hypertension (Dallas, Tex. : 1979) 20170828 4

IL-10 (interleukin-10) has been suggested to play a protective role in angiotensin II (AngII)-induced cardiovascular disorders. This study examined the role of endogenous IL-10 in salt-sensitive hypertension and renal injury induced by AngII. Responses to chronic AngII (400 ng/min per kilogram body weight; osmotic minipump) infusion were evaluated in IL-10 gene knockout mice fed with either normal salt diet (0.3% NaCl) or high salt (HS; 4% NaCl) diet, and these responses were compared with those ...[more]

PMID: 28847894

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Project description:Background:The exact mechanisms for the development of essential hypertension are not known. Activation of the renin-angiotensin-aldosterone system (RAAS) in adipose tissue may represent an important link between obesity and hypertension. This study investigates the effects of oral intake of glucose with and without NaCl on angiotensin II (AngII) and aldosterone in obese and nonobese patients with essential hypertension. Methods:Twenty newly diagnosed untreated essential hypertensive patients and 15 normotensive control subjects matched for age, gender, and BMI were studied. Participants fasted overnight (8-10?hrs), and then each subject took 75?gm glucose alone and with 3?gm NaCl, each dissolved in 250?ml. Subjects were monitored for 2 hours. Half hourly BP, plasma glucose (PG), serum Na+, K+, insulin, AngII, and aldosterone were measured. Subjects were classified into obese (BMI >30?Kg/m2) (11 patients and 8 control) and nonobese (BMI <30?Kg/m2) (9 patients and 7 control). Results:After intake of glucose with NaCl serum, AngII was significantly higher in obese hypertensive patients compared with nonobese patients (P = 0.016). Intake of glucose with NaCl resulted in a significantly higher serum Na in obese hypertensive patients compared with nonobese patients Na (P = 0.009). Serum aldosterone was significantly higher in obese patients (P = 0.03, after glucose; P = 0.003, after glucose with NaCl) and in nonobese patients (P = 0.000 and P = 0.000, respectively) compared with their respective normotensive control subjects. In obese and nonobese patients, intake of glucose and glucose with NaCl showed no significant change in the levels of serum AngII and aldosterone which was associated a significant increase in serum Na in obese patients (P = 0.03) and a highly significant reduction in serum K in nonobese patients (P = 0.001). Conclusion:Failure of suppression or inappropriate maintenance of secretion of AngII and aldosterone in both hypertensive groups by intake of glucose with NaCl may indicate a possible mechanism of essential hypertension.

Project description:UnlabelledAngiotensin II (AT-II) is a pro-fibrotic compound that acts via membrane-bound receptors (AT-1R/AT-2R) and thereby activates hepatic stellate cells (HSCs). AT-II receptor blockers (ARBs) are thus important candidates in the treatment of liver fibrosis. However, multiple case reports suggest that AT-1R blockers may induce hepatocyte injury. Therefore, we investigated the effect of AT-II and its receptor blockers on cytokine-, oxidative stress- and bile salt-induced cell death in hepatocytes. Primary rat hepatocytes were exposed to TNF-α/Actinomycin D, the ROS-generating agent menadione or the bile salts: glycochenodeoxycholic acid (GCDCA) and tauro-lithocholic acid-3 sulfate (TLCS), to induce apoptosis. AT-II (100 nmol/L) was added 10 minutes prior to the cell death-inducing agent. AT-1R antagonists (Sartans) and the AT-2R antagonist PD123319 were used at 1 µmol/L. Apoptosis (caspase-3 activity, acridine orange staining) and necrosis (Sytox green staining) were quantified. Expression of CHOP (marker for ER stress) and AT-II receptor mRNAs were quantified by Q-PCR. AT-II dose-dependently reduced GCDCA-induced apoptosis of hepatocytes (-50%, p<0.05) without inducing necrosis. In addition, AT-II reduced TLCS-induced apoptosis of hepatocytes (-50%, p<0.05). However, AT-II did not suppress TNF/Act-D and menadione-induced apoptosis. Only the AT-1R antagonists abolished the protective effect of AT-II against GCDCA-induced apoptosis. AT-II increased phosphorylation of ERK and a significant reversal of the protective effect of AT-II was observed when signaling kinases, including ERK, were inhibited. Moreover, AT-II prevented the GCDCA-induced expression of CHOP (the marker of the ER-mediated apoptosis).ConclusionAngiotensin II protects hepatocytes from bile salt-induced apoptosis through a combined activation of PI3-kinase, MAPKs, PKC pathways and inhibition of bile salt-induced ER stress. Our results suggest a mechanism for the observed hepatocyte-toxicity of Sartans (angiotensin receptor blockers, ARBs) in some patients with chronic liver injury.

Dataset Information

Evidence for Prohypertensive, Proinflammatory Effect of Interleukin-10 During Chronic High Salt Intake in the Condition of Elevated Angiotensin II Level.

Publications

Evidence for Prohypertensive, Proinflammatory Effect of Interleukin-10 During Chronic High Salt Intake in the Condition of Elevated Angiotensin II Level.

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