Role Of Tempol In The Regulation Of Renal RAS Components Of Obese-related Hypertensive Rats

Background：Cardiovascular disease is an important and serious disease affecting human health.Currently in cardiovascular disease, the incidence of hypertension shows an increasing trend.Obesity is a major risk factor of hypertension, and obesity-related hypertension attractsmore and more people’s attention. So it has an important clinical significance to prevent andtreat by elucidating the mechanism of obesity-related hypertension. In the regulation ofblood pressure, in addition to the blood vessels, heart and brain, the kidney also plays a veryimportant role in it. The kidney is a vital organ for urinary sodium excretion to regulateblood pressure.Renin-angiotensin-aldosterone system plays an important role in the regulation ofblood pressure. RAS is including a classical pathway (renin-angiotensinⅡ-angiotensinreceptor type Ⅰ) and a non-classical pathway [renin-angiotensin Ⅱ-angiotensin receptortype Ⅱand renin-Ang (1-7)-Mas receptor], which maintain a stable blood pressure bymutual adjustment. ANG II is a major RAS peptide that induces its effects by binding to twomajor receptor subtypes, AT1R and AT2R. AT1Rs are ubiquitously expressed and areinvolved in mediating vasoconstriction, antinatriuresis, contributed to an increase in bloodPressure, whereas activation of AT2Rs are associated with vasodilatation, apoptosis,antiproliferation, and natriuresis, potentially lower blood pressure, therefore, considered asfunctional antagonists to the AT1Rs. Besides, the activation of the “nonclassic pathway”(ACE2/Ang-(1-7)/Mas) opposes AT1mediated effects, leading to vasodilation and enhancepressure natriuresis. In obesity-related hypertension, the classical pathway and non-classicalpathway in renal RAS are often unbalanced, leading to an impair in natriuresis and diuresis,which causes an increase in blood pressure.Although the precise mechanism of the actions of renal RAS components imbalance inhuman and animal models of obesity-related hypertension remains to be elucidated, there is emerging evidence that obesity, aging, diabetes, and hypertension are associated withincreased oxidative stress, Oxidative Stress plays an important role in the development ofhypertension. Particularly, in obesity-related hypertension patients and animal models, thelevel of oxidative stress is significantly increased. we hypothesized that chronic antioxidanttreatment would improve the balance between classical pathway and non-classical pathwayof renal RAS system in obesity-related hypertension, which would helpful to reduce bloodpressure in obese zucker rats.Methods:1. Zucker rats given anti-oxidative stress treatment with tempol, some changes ingeneral physiological characteristics were measured in Zucker rats.24-hour urine outputand excretion of sodium were measured by placing rats in stainless steel metabolic cages.Arterial blood pressure (BP) were measured by using a CODA noninvasive tail-cuff system.The extent of MDA and SOD activity in the kidney cortex was determined by assay kit.2. The function and expression level of renal AT1receptor in Zucker rats weredetermined by adrenal arterial infusion and Westernblot, respectively.3. The function and expression level of renal AT2and Mas receptor in Zucker rats weredetermined by adrenal arterial infusion and Westernblot, respectively.Result:1. Obese Zucker rats had some significant physiological parameters of metabolicsyndrome including body weights and plasma levels of insulin, glucose, triglycerides andblood pressure were higher in obese Zucker than lean Zucker rats. However, tempoltreatment could effectively improve the above-mentioned abnormal physiologicalcharacteristics in obese Zucker rats.2. Obese Zucker rats exhibited a significant increased in oxidative stress, including therenal cortex levels of SOD were lower and the MDA higher in obese Zucker rats than leanZucker rats, however, tempol treatment could significantly lower the levels of oxidativestress.3. Obese Zucker rats had an excessive activation of classical pathway and inhibition ofnon-classical pathway in renal RAS system. Tempol treatment could regulate this imbalance,as well as reduced the expression and function of AT1receptors, further increasedexpression and function of AT2and Mas receptor in obese Zucker rats Conclusion:Tempol could reduce the level of oxidative stress in obese Zucker rats, which is helpfulto regulate the balance of renal RAS system, improve renal urinary sodium excretion andreduce blood pressure in obese zucker rats.