Effects of angiotensin II receptor antagonist on remodeling of renal arterioles in hypertension

AIM: To investigate the effects of angiotensin II receptor antagonist on remodeling of renal arterioles in hypertension. METHODS: Eighteen 4 weeks old male rats were divided into three groups: Wistar-Kyoto rats (WKY) for normotensive group, and spontaneously hypertensive rats (SHR) for hypertensive group, and SHR treated with losartan orally (15 mg·kg^-1·d^-1). The rats were raised to 16 weeks old. The morphometric parameters of the renal arterioles, and the widths of vascular smooth muscle cells (VSMC) and intercellular space were studied on kidney slices by light microscope and electromicroscope respectively, combined with computer-assistant image analysis system. The minimal renal vascular resistance (RVR_min) was studied by isolated kidney perfusion system. RESULTS: The systolic blood pressure of the tail artery, wall thickness, wall area, ratio of wall thickness to inner diameter, width of VSMC of renal arterioles and RVR_min were all smaller or lower in losartan group than those of SHR.     

Clinical studies of L-Arg effect on essential hypertension

AIM and METHODS:To investigate the effect of L-arginine -nitric oxide pathway on patients with essential hypertension via hemodynamics and neuroendocrinology. 24 essential hypertension patients were randomly divided into two groups, group I was given L-Arg, and groups Ⅱ was given normal saline as control. Blood pressure, heart rate, heart funtion, nitric oxide, angiotensinⅡ, endothelin, thromboxane A₂ and prostacyline were measure in all patients. RESULTS: In group Ⅰ arterial pressure decreased, heart rate increased, cardial output, systolic volume and eject fraction increased, total peripheral resistance decreased. NO and PGI₂ levels were inceased. But at 80 min , with NO concentration decreased, SBP,DBP were increased, TPR, FT and AngⅡ were also increased. While HR, CO, SV and EF were decreased. However TXA₂ and PGI₂ showed not much change. CONCLUSION: Exogenous L-arginine produced a vasodilatory effect by increasing NO production ,caused the change of other hemodynamic function . It also indirectly changed plasma ET, AngⅡlevels by negative feed-back and suppressed the accumulation of platelet.     

Angiotensin II regulates catalase expression and promotes fibroblast phenotype transformation through ERK1/2 pathway

AIM: To explore the effect of extracellular signal-regulated kinase 1/2 (ERK1/2) on the vascular adventitial remodeling in a hypertension rat model. METHODS: The rats were randomly divided into control group, mini-pump infusion of saline group and mini-pump infusion of angiotensin II (Ang II) group as the hypertension model. The systolic pressure and vascular morphology of the rats were examined. Adventitial fibroblasts were treated with Ang II, PD98059 (ERK1/2 inhibitor) and Ang II+PD98059. The catalase (CAT) expression in the cells was detected by Western blotting. RESULTS: Compared with control group and mini-pump infusion of saline group, the systolic pressure and carotid media thickness (stained by HE) in mini-pump infusion of Ang II group were significantly increased (P<0.01). Meanwhile, artery morphology in mini-pump infusion of Ang II group had obviously changed with a significant occurrence of pathological vascular remodeling. The result of Western blotting showed that the expression of CAT in the adventitial fibroblasts treated with Ang II+PD98059 was much higher than that in the cells treated with Ang II alone (P<0.05), indicating that down-regulation of CAT induced by Ang II was restored by ERK1/2 signaling pathway. CONCLUSION: Ang II down-regulates CAT through ERK1/2 pathway and promotes cell phenotype transformation, which lead to pathological vascular remodeling.     

Cardiac hypertrophy induced by exercise training:the function of AT1 receptor,autophagy and miRNAs

As a mechanical and exogenous stimulus, exercise training induces cardiac physiological hypertrophy, and the cardiac structure is changed slowly, steadily and coordinately. Simultaneously, energy metabolism and function of the cardiac muscle are also improved. These are positive adaptations in the heart when experiencing endurance exercise training. Recently, angiotensin Ⅱ type 1 (AT1) receptor, autophagy and miRNAs are all considered as important regulators to cardiac hypertrophy induced by exercise training at different molecular levels. Fully understanding the relations and the important role of AT1 receptor, autophagy and miRNAs in cardiac physiological hypertrophy will further enrich the signaling pathway of cardiac hypertrophy induced by exercise training.     

Effects of AT1 receptor autoantibody on renal cell apoptosis and JNK expression in diabetic nephropathy rats

AIM:To study the effects of angiotensin Ⅱ type 1 receptor autoantibody (AT1-AA) on the apoptosis of renal cell and the expression of c-Jun N-terminal kinase (JNK) in diabetic nephropathy (DN) rats. METHODS:High-sucrose and high-fat diet and intraperitoneal injection of streptozotocin were utilized to induce DN rat model. We employed enzyme-linked immunosorbent assay (ELISA) for serum AT1-AA and TUNEL staining for renal cell apoptosis. Furthermore, Western blotting was performed to measure the levels of endoplasmic reticulum stress (ERS) chaperone glucose-regulated protein 78 (GRP78) and ERS-associated apoptosis protein p-JNK. RESULTS:The renal cell apoptotic rate in DN group was significantly increased compared with NC group, and the apoptotic renal cells in AT1-AA positive DN rats were much greater than those in AT1-AA negative DN rats (P<0.05). The protein levels of GRP78 and p-JNK were significantly increased compared with NC group. GRP78 and p-JNK protein levels also significantly increased in AT1-AA positive DN rats compared with AT1-AA negative DN rats. CONCLUSION: AT1-AA activates ERS response and induces renal cell apoptosis via the JNK apoptotic pathway in the renal tissues of DN rats.     

Diuretic mechanism of U50 488H in spontaneously hypertensive rats

AIM: To investigate the diuretic effects of U50 488H, a selective κ-opioid receptor agonist, in spontaneously hypertensive rats (SHR) and explore their mechanism. METHODS: The physiological experimental technique was used to measure the blood pressure (BP), and the volume of urine output in normatensive WKY (Wistar-Kyoto) rats and SHR was measured. The plasma levels of some humoral factors were detected by radioimmunoassay. RESULTS: U50 488H decreased BP significantly in WKY rats and SHR, and the decrease of BP in SHR was more than that in WKY rats. U50 488H increased the urine volume dose-dependently in WKY rats and SHR. The urine volume of SHR increased by U50 488H was more than that of WKY rats. U50 488H (1 mg/kg) produced marked decrease in plasma concentration of ADH in WKY rats and SHR, and the decrease in SHR was significantly stronger than that in WKY. U50 488H also induced a decrease in plasma concentration of AngⅡin SHR, while it had no influence on the plasma concentration of AngⅡ in WKY rats. These effects of U50 488H were abolished by nor-BNI, a selective κ-opioid receptor antagonist. CONCLUSION: The significant decreases in plasma concentration of ADH and AngⅡmay be responsible for the effective diuresis of κ-opioid receptor stimulation by U50 488H in SHR.     

Roles of Rho-kinase in rat cardiac fibroblasts proliferation and collagen synthesis induced by angiotensin Ⅱ

AIM: To investigate the role of Rho-kinase signal pathway in rat cardiac fibroblasts (CFBs) proliferation and collagen synthesis induced by angiotensinⅡ (AngⅡ). METHODS: CFBs of neonatal Sprague-Dawley (SD) rats were isolated with the method of trypsin digestion and differential anchoring velocity. The CFBs were stimulated with AngⅡto induce fibrosis. Proliferation of CFBs was observed by MTT coloricmetric assay. Synthesis of collagen was detected by the hydroxyproline. The expression of Rho-kinase mRNA was examined using RT-PCR analysis. The extent of phosphorylation of myosin-binding subunit (MBS-P) of myosin phosphatase was quantified by Western blotting analysis, which was used to evaluate the activity of Rho-kinase.RESULTS: (1) Stimulation of neonatal SD rat CFBs with AngⅡ (10-7 mol/L) significantly increased CFBs proliferation and collagen synthesis (P<0.01). (2）Stimulation of neonatal SD rat CFBs with AngⅡ (10-7 mol/L) significantly increased the expression of Rho-kinase mRNA and rapidly activated Rho-kinase in a time-dependent manner. (3) Within a concentration coverage, hydroxyfasudil (H4413), a Rho-kinase inhibitor, effectively inhibited AngⅡ-induced CFBs proliferation and collagen synthesis (P<0.05 or P<0.01).CONCLUSION: Rho-kinase signal pathway may be one of the most important signal transducter for AngⅡ-induced CFBs proliferation and collagen synthesis in neonatal SD rats.     

Effect of irbesartan on nephrin expression in the podocyte of early diabetic nephropathy rats

AIM: To investigate the expression of the nephrin in podocyte of the diabetic nephropathy(DN) rats and the mechanism of irbesartan-induced renal protection.METHODS: The DN model was established by a single injection of streptozotocin(STZ),and DN rats were randomly divided into 2 groups: model group and irbesartan treatment group.In addition,the normal rats served as a normal control group. All the rats were received daily gavage respectively for 8 weeks. The urinary protein quality in 24 hours,body weight(BW),kidney weight (KW),KW/BW,glucemia,urea nitrogen,creatinine,total cholesterol, triacylglycerol were detected with correlative methods and the pathological changes of kidney were also detected with optic microscope and transmission electron microscope.The expression of nephrin in podocyte were detected by immunohistochemistry. RESULTS: In DN rats, irbesartan reduced the urinary protein quality in 24 hours (P<0.01) and alleviated the damage of kidney. Meanwhile，the expression of nephrin was declined remarkably in podocytes in irbesartan treatment group compared with model group（P<0.05）.CONCLUSION: Irbesartan might protect kidney against STZ-induced injury via decreasing the expression of nephrin in podocytes.