It’s Time for New Insights into Renovascular Hypertension at the Molecular Level

At the cellular level, reduced kidney perfusion in atherosclerotic renal arthery disease (ARVD), induces hypoxia, activation of the renin-angiotensin-aldosterone system (RAAS) and cytokine activation. Impaired blood flow in the kidneys creates a microenvironment triggering significant cytokine production, contributing to vascular damage and endothelial disfunction. Interactions between cytokines and endothelial, glomerular, and tubular cells often result in increased vessel permeability, and fibrosis, and contribute to the development of chronic kidney disease (CKD). Molecules such as endothelins, prostaglandins, and nitric oxide play a crucial role at the molecular level. The imbalance between vasoconstrictor and vasodilator factors contributes to vascular dysfunction. Oxidative stress and inflammatory processes at the cellular level contribute to endothelial damage and structural changes in blood vessels. Mineralocorticoid receptor antagonists (MRAs) therapy in the context of ARVD holds promise in reducing fibrosis, promoting angiogenesis and enhancing overall outcomes in patients with this pathology. Recent data also indicates the antioxidative, anti-inflammatory, and antifibrotic effects of SGLT2 inhibitors. They reduce oxidative stress caused by hypoxic conditions and enhance renal perfusion, contributing to the preservation of cellular function. Studies employing Blood Oxygen Level-Dependent (BOLD) imaging have identified adaptations to reduced blood flow, volume, and glomerular filtration rate in post-stenotic kidneys that preserve oxygenation in the medulla and cortex during medical therapy. Data from the literature indicate that despite the partial recovery of renal hypoxia and restoration of blood flow after revascularization, inflammatory cytokines and injury biomarkers remain elevated, and the glomerular filtration rate (GFR) does not recover in ARVD. Restoration of vascular patency alone has failed to reverse tubulointerstitial damage and partially explains the limited clinical benefit of renal stenting. Considering these findings, BOLD MR imaging emerges as a technique capable of providing insights into the critical juncture of irreversibility in ARVD. However, further research is needed to monitor renal hypoxia following renal artery stenting and the inflammatory response over an extended period in conjunction with optimal therapy involving MRAs and SGLT2 agonists. The aim of research at the molecular level enables the identification of potential therapeutic modalities targeting specific molecular pathways, opening the door to innovative approaches in treating renovascular hypertension.

Renovascular hypertension causes cerebral vascular remodeling

Renovascular hypertensive rats （RHRs） were developed using the 2-kidney, 2-clip method. All RHRs at 10 weeks displayed high permeability of the cerebral surface blood vessels. Vascular casts of the RHRs showed that the vascular network was sparse. The arterioles of the RHRs at 10 weeks had smaller lumen diameters, but thicker vessel walls with hyalinosis formation compared with control animals. The endothelial cell membrane appeared damaged, and microthrombus formed. After ischemia, the infarction size was larger in RHRs than in control animals. These results suggest that cerebral arterioles in RHRs underwent structural remodeling. High blood pressure may aggravate the severity of brain injury in cerebral ischemia and affect the recovery of ischemia.

Gene expression profiles in the peri-infarct brain cortex in a rat model of stroke-prone renovascular hypertension

BACKGROUND： Previous studies have focused on gene expression acutely following stroke onset. However, there have been a few reports of gene expression during later stages of cerebral infarction. OBJECTIVE： To determine gene expression profiling in the peri-infarct brain cortex 7 days after ischemia in a rat model of cerebral infarction in renovascular hypertensive rats. DESIGN, TIME AND SETTING： An in vivo, molecular experiment was performed at the Experimental Animal Center of Sun Yat-sen University and CapitalBio, Beijing, China between February 2004 and August 2005. MATERIALS： A 70-mer oligo chip containing 5 705 rat genes was supplied by CapitalBio, Beijing, China; and the Oligo rat gene bank was provided by Qiagen, the Netherlands. METHODS： Six Sprague Dawiey rats were utilized to establish a stroke-prone renovascular hypertensive model using the two-kidney and two-clip method. The rats were subsequently randomly assigned to two groups： middle cerebral artery occlusion and sham-operation, with three rats in each group. The middle cerebral artery occlusion model was induced by intraluminal suture method. Incisions were sutured following isolation of carotid arteries in the sham-operation group. MAIN OUTCOME MEASURES： Total RNA was extracted from the peri-infarct cerebral cortex 7 days after surgery. Following fluorescent labeling, RNA was hybridized to an Oligo chip containing 5 705 genes and was then scanned. Images were collected and the differentially expressed genes （number and category） were selected by data analysis. RESULTS： A total of 174 genes were upregulated, and 23 were downregulated, in the peri-infarct cerebral cortex 7 days after ischemia. The upregulated genes were distributed among 12 functional categories, and the downregulated genes belonged to categories of transport, transcription regulators, signals, response to stress, metabolism, and cell adhesion. The expression of some cytoskeletal genes was upregulated, including VIM, A2M, B2M, ACTR3, and ARPClB. Expression of a few cell adhesion-related genes （such as NLGN1, LGALS1, LGALS3, COLIA1, COL2A1, and SPP1） and other inflammation-related genes （such as CIQB, ClS, C4, C5R1, CFH, CD14, CD164, CD47, CD48, CD53, CD8B, IFNGR, and TFITM2） were upregulated. The glutamate-receptor gene GRIK5 was downregulated, which is related to the excitatory neurotransmitter glutamate. However, expression of the inhibitory neurotransmitter GABA-related genes was bidirectional - namely, GABRA5 downregulation and GABARAP upregulation. CONCLUSION： Upregulation of many cell adhesion and inflammation related genes and downregulation of excitatory glutamate-related receptor genes revealed active gene expression during later stages of cerebral infarction, which suggested molecular mechanisms of injury or repair.

Effect of chrysanthemum extract on myocardial fibrosis in rats with renovascular hypertension

OBJECTIVE: To investigate the inhibitory effect of chrysanthemum extract on myocardial fibrosis in rats with renovascular hypertension, and explore the possible mechanism underlying this effect.METHODS: Sixty Wistar rats were randomly divided into six groups: sham operation, model, positive control, and low-, medium-, and high-dose Huai chrysanthemum extract groups(ten rats per group). With the exception of the sham operation group, a renal hypertensive model was established in rats using the 'two-kidney, one clip' method. After 6 weeks, low-, medium-, and high-dose groups were intragastrically administered chrysanthemum extract at 1, 2, or 4 g/kg, respectively, once daily for 4 weeks. The positive control group was administered Kato Pury at 50 mg/kg once daily for 4 weeks,while sham operation and model groups received an equal volume of distilled water once daily for 4 weeks. Blood pressure changes were examined before modeling, 6 weeks after modeling, and after 4 weeks of treatment administration. Ventricular remodeling indexes were measured by high frequency echocardiography after 4 weeks of treatment administration. Pathological changes were observed by hematoxylin and eosin, and Masson’s trichrome staining methods. Collagen type sion were eⅠxa(Col minedⅠ) and type Ⅲ(Col Ⅲ) expres by enzyme-linked immunosorbent assays. Transforming growth factor-β1(TGF-β1), sma mad 3(Smad3),Smad7, Ras homolog gene family, member A(RhoA), and Rho-associated protein kinase 1(ROCK1) protein expression were detected by Western blot.RESULTS: Compared with the model group, chrysanthemum-administered groups and the positive control group showed significant improvement of arterial blood pressure, echocardiography indicators, and degree of myocardial fibrosis(P < 0.05). In addition, these groups exhibited decreased expression of Col Ⅰ, Col Smad3, and increaseⅢ, RhoA, ROCK1, TGF-β1, and d Smad7 expression. Such improvements were most obvious in the high-dose chrysanthemum extract group(P < 0.05).CONCLUSION: Chrysanthemum extract could effectively reduce myocardial fibrosis in rats with renovascular hypertension by a mechanism that potentially involves inhibition of RhoA/ROCK1 and TGF-β1/Smad signaling pathways.

Effects of RNA interference targeting angiotensin 1a receptor on blood pressure and cardiac hypertrophy of rats with renovascular hypertension

The aim of this study is to investigate the effects of RNA interference(RNAi)targeting angiotensin 1a receptor(AT1a)on blood pressure and cardiac hypertrophy of rats with renovascular hypertension.Two RNAi plasmids,pAT1a-shRNA1 and pAT1ashRNA2 each carrying a U6 promoter and an AT1aspecific shRNA-coding template sequence corresponding to the sites 928-946,978-996 of the mRNA transcript,and a control plasmid pCon carrying a nonspecific shRNA-coding sequence were constructed.Thirty Sprague-Dawley rats with renovascular hypertension(2-kidney 1-clip)were randomly divided into 5 equal groups:Control group(without any intervention),pAT1a-shRNA1,pAT1a-shRNA2,pCon groups(with injection of the corresponding plasmid 4 mg/kg respectively into the tail vein),and valsartan group(30 mg/kg·d^(-1) by gavage).Three weeks after drug administration,pAT1a-shRNA1,pAT1a-shRNA2 and valsartan respectively resulted in decrease of the tail blood pressure by(15.1±5.4),(16.4±8.4)and(30.6±18.2)mmHg.However,the tail blood pressure increased further by about 25 mmHg in both of pCon and control groups.The carotid artery pressures of pAT1a-shRNA1,pAT1ashRNA2 and valsartan groups were all significantly lower than those of the control and pCon groups.The ratio of left ventricle weight to body weight(LV/BW)of the rats in pAT1a-shRNA1,pAT1a-shRNA2,and valsartan groups decreased significantly than in the control group(P<0.01),similar to those of the normal SD rats(P>0.05).Histopathological examination showed that the myocardiocytes were significantly hypertrophic and the basal membrane of the aorta was significantly thickened in the control group and such changes were alleviated in the pAT1a-shRNA1,pAT1a-shRNA2 and valsartan groups.Compared with the control group,pAT1a-shRNA1 and pAT1a-shRNA2 groups had lowered expression of AT1 receptor(in the myocardium and the thoracic aorta(all P<0.01);however,there were no significant differences in expression levels of AT1 receptor in valsartan and the control groups(P>0.05).We conclude that RNAi targeting AT1a receptor inhibits the development of renovascular hypertension and the accompanying cardiac hypertrophy.RNAi technology may become a new strategy of gene therapy for hypertension.

Expression of neurocan mRNA and ultrastructure of brain tissue after cerebral ischemia and reperfusion in stroke-prone renovascular hypertensive rats treated by electroacupuncture

We established a stroke-prone renovascular hypertensive rat model by bilateral constriction of the renal artery with sliver loop clips. After ten weeks, middle cerebral artery occlusion was induced for 2 hours. The rats then received electro-acupuncture at Baihui （DU 20） and Dazhui （DU 14） after onset of ischemia for 30 days. In situ hybridization study showed that electroacupuncture significantly reduced the number of neurocan mRNA-positive cells in the ischemic penumbra and hippocampal tissues of rats. Electron microscopy results demonstrated that the structure of neurons and blood vessels in the ischemic tissues were restored with electroacupuncture. Overall, these data suggest that electroacupuncture may protect neurons against ischemic reperfusion injury in stroke-prone renovascular hypertensive rats, which may be regulated by downregulation of expression of nerve inhibitory factor neurocan mRNA.

Artificial cold exposure induced stroke in renovascular hypertensive rats and its association with cold-inducible RNA binding protein mRNA expression in brain tissue and blood pressure

BACKGROUND： High incidence of stroke at interchange period of autumn and winter was demonstrated by epidemiological survey, and the specific causes should be further investigated. OBJECTIVE： To investigate the influence of artificial cold exposure on the incidence of stroke in renovascular hypertensive rats （RHR）, and analyze the association with blood pressure and cold-inducible RNA binding protein （CIRP） mRNA expression in brain tissue. DESIGN： A completely randomized grouping design, a randomized control animal trial. SETTINGS： Lab of Neurology, the First Affiliated Hospital of Sun Yat-sen University; Department of Chemistry, Open laboratory of Chemical Biology, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong. MATERIALS： Male SD rats （n=460）, weighing 80 - 100 g were obtained from Guangdong Province Health Animal Unit. A modified RXZ-300A intelligent artificial climate cabinet （Ningbo Jiangnan Instrument Co. ,Ltd., China）. METHODS： The experiment were processed in the Lab of Neurology, the First Affiliated Hospital of Sun Yat-sen University and the Open Laboratory of Chemical Biology, Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong from October 2004 to November 2005. Rats （n = 400） were operated to establish 2-kidney 2-clip RHR model as described previously. The sham-operated rats （n =60） served as normotensive controls. Eight weeks later, 300 of RHR were randomly selected according to their systolic blood pressure （SBP） and divided into 3 sub-groups （n =100 per group）： mild hypertensive group （SBP of 160 - 200 mm Hg）, moderate hypertensive group （SBP of 200 - 220 mm Hg） and severe hypertensive group （SBP 〉 220 mm Hg）. Each group was further divided into two groups （n =50） under ACE and non-ACE. Normal sham-operated SD rats （n =60）, SBP 〈 140 mm Hg, were randomly divided into two groups： Sham-operated control group （n =30） under ACE and non-ACE. To establish the ACE and non-ACE treatment, rats were housed individually in artificial climate cabinet, and ACE was designed as three cycles of 12-hour light of 22℃ （7 ： 00 - 19 ： 00） and 12-hour dark of 4℃（19 ： 00 - 7 ： 00）. The non-ACE group was kept at 22℃ throughout the experiment. MAIN OUTCOME MEASURES： Blood Pressure changes were measured and stroke symptom were observed; Expression of the CIRP were examined by reverse transcription-polymerase chain reaction. RESULTS： Finally 360 rats were involved in the analysis of results. ①Incidence of stroke： The incidence of stroke in 2k2c RHR was significantly higher after a three-day intermittent （12-hour） ACE （29.3%） as compared with that in non-ACE （17.3%） （P 〈 0.05）. Furthermore, the severe hypertensive 2k2c RHR （BP 〉 220 mm Hg） was found to have much higher incidence of stroke （66%, 33/50） than the mild （8%, 4/50） and moderate （18%） hypertensive 2k2c RHR. ②CIRP mRNA in brain tissue： ACE treatment stimulated the mRNA expression of CIRP in non-stroke 2k2c RHR but not in stroke 2k2c RHR （P 〈 0.05）. CONCLUSION： High blood pressure and low expression of CIRP are associated with ACE induced stroke.

Anti-hypertensive effects of rosiglitazone on renovascular hypertensive rats:role of oxidative stress and lipid metabolism

This study investigated the anti-hypertensive mechanismof rosiglitazone in renovascular hypertensive rats,and examined its relationship to oxidative stress and lipid metabolism. The renovascular hypertension was induced by stenosis of the left renal artery. Four groups of rats were selected： control,induced untreated,rosiglitazone（ 20 mg / kg） and captopril（ 10 mg / kg）. After 14 d of administration,compared with induced untreated group,rosiglitazone group reduced the renovascular hypertensive rats ＇ systolic blood pressure and diastolic blood pressure,and decreased total cholesterol（TCH）,triglyceride（TG）,angiotensin II（ Ang II） and angiotensin receptor（ AT1） levels（ P ＆lt; 0. 05）. Meanwhile,rosiglitazone remarkably decreased the levels of malondialdehyde（ MDA） and hydrogen peroxide（ H2O2） while improved the levels of supperoxide dismutase（ SOD） and reduced glutathione（ GSH）. These results suggested that rosiglitazone could effectively decreased the blood pressure in renovascular hypertensive rats,and this might be performed by regulating the activity of angiotensin and the lipid metabolismand improving the oxidative stress.

Proximal Iliac Artery Stenosis in Allograft Renal Transplant, a Diagnostic beyond Echo-Doppler, Treatment Approach

Background: Transplant Renal Artery Stenosis (TRAS) is a well-known vascular complication after a kidney transplant. It is associated with premature renal failure, uncontrolled hypertension, and allograft loss. However, Proximal Iliac Artery Stenosis to a Kidney Transplant (Prox-TRAS) is an uncommon cause of vascular graft complication leading to acute renal failure and refractory hypertension with a less incidence around and only a few cases reports have been described in the medical literature. Methods: We reviewed the medical record of kidney transplant recipients of the General Hospital of Ciudad Real, Spain, from March 2008 to March 2019. We identified all cases (260) with the diagnosis of renal vascular hypertension by imaging studies. Of those 260 renal vascular stenoses, five (5) were diagnosed with proximal iliac artery stenosis through Angio-CT and arteriography. We performed an analysis of clinical parameters and evolution. Results: Prox-TRAS was diagnosed in 5 of the 260 patients who presented acute or progressive allograft dysfunction with refractory hypertension, with an incidence rate of 1.4%. In 4 of them (1.1%), we had to resort to another imaging test, angio-CT, arteriography, as the echo-doppler was unable to identify the abnormalities. Hypertension was a constant finding along with impaired renal function (100%);with respect to Prox-TRAS, its onset was later (12 - 60 months) after transplantation. An increase in TA (140 ± 10 and 80.7 ± 7 to 160 ± 18 and 85 ± 7 mmHg, p-0.009) was observed. There was an increase in the use of hypotensive drugs (2.1 ± 1.1 and 4.3 ± 1, p-0.003). Similarly, in all cases, a worsening of basal creatinine from 0.9 to 0.1 ± to 1.2 ± (P × 0.004) was also observed. Prox-TRAS was a cause of the increase in both creatinine and TA (140 ± 10 and 80.7 ± 7 to 160 ± 18 and 85 ± 7 mmHg, P 0.009). All cases were treated by Percutaneous transluminal angioplasty with stent placement, N= 5. In the follow-up, improvement was obtained from the claudication clinic as well as renal function and blood pressure, CRB (from 2.7 ± 1.4 to 1.8 ± 0.4 mg/dL, P-0.02) and TA (160 ± 18/85 ± 7mmHg at 138 ± 7/82 ± 9, p 0.018). Kidney function, blood pressure remained unchanged during follow-up (130 ± 36 months). Conclusion: Through these cases review, we propose highlighting the importance of extending imaging studies to the iliac artery of the kidney graft in case of high suspected renal vascular hypertension;showing the role and safety of angioplasty as a reasonable and effective treatment in the identified cases. We assessed the possibility of the limited role of Duplex Sonography (DS) regarding clinical and angiographic. PTA is the appropriate initial treatment of Prox-TRAS, with low morbidity and mortality rates, achieving improvement of graft function and amelioration of hypertension.

Percutaneous transluminal renal angioplasty with stent is effective for blood pressure control and renal function improvement in atherosclerotic renal artery stenosis patients

Background Percutaneous transluminal renal angioplasty with stent is an effective procedure for atherosclerotic renal artery stenosis. However, the decision to perform this procedure has recently raised considerable debate. The aim of this study was to assess the effects of percutaneous transluminal renal angioplasty with stent in atherosclerotic renal artery stenosis patients, especially as it relates to blood pressure control and renal function improvement. Methods A retrospective analysis was made of the clinical data from 125 atherosclerotic renal artery stenosis patients who underwent percutaneous transluminal renal angioplasty from July 2004 to June 2008 in the Department of Vascular Surgery of Beijing Chaoyang Hospital. We compared blood pressure, number of oral antihypertensive medications, and renal function changes pre and post-procedure at 24 months follow-up. Results A total of 125 atherosclerotic renal artery stenosis patients underwent percutaneous transluminal renal angioplasty and 143 stents were placed. At 24 months follow-up, both systolic and diastolic blood pressure and the number of oral antihypertensive medications were significantly reduced （P 〈0.05）. Overall, the estimated glomerular filtration rate did not change significantly （P〉0.05）; however, a significant increase in estimated glomerular filtration rate was observed in the subgroup of patients with a lower baseline estimated glomerular filtration rate and in the subgroup of patients with bilateral renal artery stenosis （P 〈0.05）. Conclusion Percutaneous transluminal renal angioplasty patients, providing a significant improvement in blood antihypertensive medications. s a safe procedure for atherosclerotic renal artery stenosis pressure control and reduction in the number of oral

Effects of atorvastatin on cardiovascular remodeling in 2-kindey and 1-clip hypertensive rats

Background Nowadays, the studies mainly focus on the function of decreasing the inflammatory factor and improving the functions of endothelium, but the Methods The 2-kindey, 1-clip hypertensive rats effects of statins on ventricular remodeling are rarely studied. （2K1C, Goldblatt） were prepared with Sprague-Dawley （SD） rat. SD rats were randomly divided into three groups： control rats, hypertensive rats and hypertensive rats treated with atorvastatin （2 mg·kg^-1·d^-1）. After 6 weeks, systolic blood pressure （SBP） was measured using the tail-cuff method. The plasma concentration of angiotensin Ⅱ and renin activity were determined by radioimmunoassay. The heart weight, the ratio of left ventricular weight and body weight was calculated. Results The plasma concentration of angiotensin Ⅱ （106.4±7.8） ng/L and renin activity （20.6±2.4） ng/L were significantly increaed in hypertensive rats compared with normal rats [ （72.3±5.4） ng/L and （12.5±3.7） ng/L] （P 〈 0.01）. The heart weight （1.46 ± 0.09）g, the ratio 3.54±0.19 （ × 10^-3） of left ventricular weight and body weight in hypertensive rats were obviously higher than that in normal rats [（0.98±0.07）g and （2.28 ± 0.06） × 10^-3] （P 〈 0.01）. After treatment with atorvastatin, the plasma concentration of angiotensin Ⅱ （68.3 ± 6.9） ng/L and renin activity（8.7 ± 2.3 ）ng/L, heart weight（1.05± 0.04）g, the ratio 2.36 ± 0.07 （×10^-3） above were decreased significantly, there were no difference between the group of hypertensive rats and the normal. Conclusions Atorvastatin can decrease the ratio of left ventricular weight and body weight and has the effects on cardiovascular remodeling in hypertensive rats.