A simple, refined approach to diagnosing renovascular hypertension in children: A 10-year study.

BACKGROUND: Despite advances in non-invasive vascular imaging, detection of renal artery stenosis via catheter angiography is the criterion standard for the diagnosis of renovascular hypertension (RVH). However, because of lack of evidence, the utility of various blood tests and imaging modalities remains unclear. METHODS: We retrospectively analyzed the utility of blood tests (plasma renin activity [PRA], aldosterone, and renal vein renin [RVR] values) and imaging studies (computed tomography angiography [CTA], kidney ultrasonography [US]) by comparing them with catheter angiography. Ten pediatric patients with RVH at two institutions from January 2008 to December 2017 were recruited. The sensitivities for diagnosing RVH via imaging and blood tests (kidney [US], PRA, and aldosterone) were derived by examining patient records. Furthermore, the sensitivity and specificity of CT angiography were calculated by considering both the affected and non-affected renal arteries of the patients. RESULTS: A high sensitivity for diagnosing RVH via kidney US (89%) and PRA (80%) was observed. The sensitivity and specificity of CTA were 100%, each. RVR sampling did not aid in the diagnosis of RVH; only two of six patients with unilateral RVH showed significant laterality of RVR boundary ratios. Renal scintigraphy facilitated detection of a non-functional kidney (split renal function <5%). CONCLUSIONS: RVH in children could be diagnosed utilizing non-invasive blood and imaging tests, without catheter angiography. We recommend kidney length measurement along with measurement of PRA level, as a simple and highly useful screening test, followed by CTA as a diagnostic test.

Collagen IV, a promising serum biomarker for evaluating the prognosis of revascularization in a 2-kidney, 1-clip hypertensive rat model.

OBJECTIVES: The goal of this study was to investigate the expression of serum collagen IV and its value for evaluating the prognosis of revascularization in a 2-kidney, 1-clip hypertensive rat model. METHODS: A total of 40 Sprague-Dawley rats were randomly and evenly divided into a control group and 3-, 10- and 20-day (D) groups (namely, the ischaemic time for 3, 10 and 20 days, respectively). The systolic blood pressure and laboratory values such as serum creatinine and collagen IV levels were measured before and after clipping the renal artery. Histological Masson staining and immunohistochemical staining of collagen IV were conducted in a kidney specimen from each group to assess the severity of renal fibrosis and the level of collagen IV expression. RESULTS: After clipping, systolic blood pressure in the 3D, 10D and 20D groups increased significantly from 108 ± 8 to 126 ± 7 and from 153 ± 8 to 157 ± 6 mmHg, respectively (10D vs 20D group, P = 0.224; between other groups, P < 0.001). The expression of serum creatinine in the 3D, 10D and 20D groups increased significantly from 35.39 ± 5.64 to 57.53 ± 7.05, 101.86 ± 8.94 and 119.76 ± 9.37 mmol/l, respectively (between each group: P < 0.001). Serum collagen IV levels in the 10D and 20D groups increased significantly from 38.5 ± 10.4 to 60.8 ± 15.0 and 87.3 ± 11.5 ng/ml, respectively (control vs 3D group, P = 0.718; between other groups, P < 0.001). The Masson staining indicated that sclerotic changes in the glomeruli of the 10D and 20D groups significantly increased from 2.20 ± 1.03 to 15.20 ± 5.03 and 28.20 ± 7.07%, respectively (control vs 3D group, P = 0.175; between other groups, P < 0.001). The grade of tubulointerstitial damage in the 3D, 10D and 20D groups increased significantly from 0.30 ± 0.48 to 1.90 ± 0.74, 1.80 ± 0.79 and 3.20 ± 0.79, respectively (3D vs 10D group, P = 0.755; between other groups, P < 0.001). The semi-quantification from immunohistochemical staining indicated that the percentage of collagen IV positive areas in the 3D, 10D and 20D groups increased significantly from 3.50 ± 1.58 to 8.60 ± 2.11, 16.60 ± 8.55 and 23.10 ± 6.15, respectively (control vs 3D group, P = 0.043; 3D vs 10D group, P = 0.002; 10D vs 20D group, P = 0.011; between other groups, P < 0.001). The area under the curve of the receiver operating characteristic curve was 0.783 (P = 0.008; 95% confidence interval 0.634-0.932). There were positive associations of serum collagen IV levels with systolic blood pressure, serum creatinine and collagen IV quantification in kidney with correlation coefficients of 0.665, 0.775 and 0.628, respectively (P < 0.001). CONCLUSIONS: As the clear ischaemia time-response relationship identified in our study indicates, the increase in serum collagen IV levels may be a satisfactory biomarker to indicate a poor prognosis of renal artery revascularization in a 2-kidney, 1-clip hypertensive rat model. However, it is perhaps not a good early biomarker for the early detection of renovascular hypertension.

Senescent Kidney Cells in Hypertensive Patients Release Urinary Extracellular Vesicles.

Background Hypertension may be associated with renal cellular injury. Cells in distress release extracellular vesicles (EVs), and their numbers in urine may reflect renal injury. Cellular senescence, an irreversible growth arrest in response to a noxious milieu, is characterized by release of proinflammatory cytokines. We hypothesized that EVs released by senescent nephron cells can be identified in urine of patients with hypertension. Methods and Results We recruited patients with essential hypertension (EH) or renovascular hypertension and healthy volunteers (n=14 each). Renal oxygenation was assessed using magnetic resonance imaging and blood samples collected from both renal veins for cytokine-level measurements. EVs isolated from urine samples were characterized by imaging flow cytometry based on specific markers, including p16 (senescence marker), calyxin (podocytes), urate transporter 1 (proximal tubules), uromodulin (ascending limb of Henle's loop), and prominin-2 (distal tubules). Overall percentage of urinary p16+ EVs was elevated in EH and renovascular hypertension patients compared with healthy volunteers and correlated inversely with renal function and directly with renal vein cytokine levels. Urinary levels of p16+/urate transporter 1+ were elevated in all hypertensive subjects compared with healthy volunteers, whereas p16+/prominin-2+ levels were elevated only in EH versus healthy volunteers and p16+/uromodulin+ in renovascular hypertension versus EH. Conclusions Levels of p16+ EVs are elevated in urine of hypertensive patients and may reflect increased proximal tubular cellular senescence. In EH, EVs originate also from distal tubules and in renovascular hypertension from Henle's loop. Hence, urinary EVs levels may be useful to identify intrarenal sites of cellular senescence.

Hematological indices in renovascular hypertension: A propensity score matching analysis.

OBJECTIVE: Various hematological blood count parameters, including the neutrophil-to-lymphocyte ratio (NLR) and mean platelet volume (MPV), were analyzed to assess differences in patients with renovascular (RVH) and essential hypertension (EH). METHODS: A propensity score analysis was performed to match 51 patients with RVH and 173 patients with EH. After matching, 49 pairs of patients were compared. RESULTS: Before matching, patients with RVH had significantly higher NLR values [1.35 (range: 1.14-1.76) vs. 1.05 (range: 0.81-1.3); p<0.001] and MPV [8.7 fL (range: 8.3-9.5 fL) vs. 8.4 fL (range: 7.3-9.2 fL; p=0.002]. After propensity score matching was performed (49 vs 49 patients), age, sex, atherosclerosis risk factors, frequency of atherosclerosis, and the medications used were similar between groups. The NLR was significantly greater in patients with RVH [1.00 (range: 0.76-1.40) vs 1.35 (range: 1.15-1.75; p<0.001]. The MPV did not differ significantly between groups. The NLR was the only parameter independently associated with RVH in a multivariate logistic regression [odds ratio: 5.563, 95% confidence interval (CI): 2.089-14.814; p≤0.001]. Receiver operating characteristic curve analysis results indicated that NLR >1.16 predicted RVH with a sensitivity of 72% and a specificity of 60% [area under curve: 0.724, 95% CI: 0.624-0.823; p≤0.001]. CONCLUSION: The results of the present study demonstrated that NLR, which is a simple, clinical parameter of inflammation, was elevated in patients with RVH.

Diagnostic Role of Renal Doppler Ultrasound and Plasma Renin Activity as Screening Tools for Renovascular Hypertension in Children.

OBJECTIVES: The diagnostic role of an ultrasound (US) and plasma renin activity (PRA) combination is unknown, despite the usefulness of Doppler US as a screening tool for renovascular hypertension (RVHT). The purpose of this study was to evaluate the diagnostic usefulness of US for RVHT in children stratified according to PRA. METHODS: We identified 336 children who underwent renal Doppler US examinations for hypertension and divided them into a high-renin group (n = 177) and a normal-renin group (n = 159) based on PRA and stratified them by age. The Doppler US findings were retrospectively reviewed, and computed tomographic angiography (CTA) for the same children was used as the reference standard. RESULTS: In the high-renin group, 36 patients had positive Doppler US findings that were confirmed by CTA in 32 cases. The sensitivity and specificity values for Doppler US in the high-renin group were 84.2% and 93.6%, respectively. In the normal-renin group, 10 patients had positive Doppler US findings; these positive findings were confirmed by CTA in 9 cases. The sensitivity and specificity values for US in the normal-renin group were 100.0% and 100.0%. There were anatomic variations (n = 3) and segmental artery stenosis (n = 2) among the cases with false-negative US findings, which were confirmed by CTA. CONCLUSIONS: If patients have high PRA, a Doppler US examination should be performed with caution to avoid false-negative detection. If patients have normal PRA, renal Doppler US might be adequate for diagnosis of RVHT to avoid unnecessary CTA.

Unilateral renal artery stenosis presented with hyponatremic-hypertensive syndrome - case report and literature review.

BACKGROUND: Renal artery stenosis is one of the secondary causes of pediatric hypertension. Cases with critical unilateral renal artery stenosis manifesting with the hyponatremic hypertensive syndrome are rare and a comprehensive description of this disorder in the pediatric population is lacking in the literature. CASE PRESENTATION: We describe a 4-year-old boy who presented with severe hypertension, profound hyponatremia, hypokalemia, nephrotic range proteinuria, and polyuria. Distinctly, the diagnosis of hyponatremic hypertensive syndrome secondary to unilateral renal artery stenosis was confirmed in light of laboratory and radiographic findings of severe natriuresis, elevated renin, and unilateral small kidney. Two weeks following nephrectomy, there was resolution of hyponatremia, hypokalemia, nephrotic range proteinuria and hypertension. CONCLUSIONS: Findings of hyponatremia, hypokalemia, hypertension, polyuria, and unilateral renal hypoplasia can be attributed to a unifying pathology of unilateral renal artery stenosis.

Diuretic herb Gomphrena celosioides Mart. (Amaranthaceae) promotes sustained arterial pressure reduction and protection from cardiac remodeling on rats with renovascular hypertension.

ETHNOPHARMACOLOGICAL RELEVANCE: Gomphrena celosioides Mart., belonging to the Amaranthaceae family, is a weed known as "perpétua," and its ethnopharmacological use is to treat of urinary tract disorders and kidney stones. Urinary tract disorders and kidney stones could include several pathological conditions such hypertension, diuretic and lithiasic problems. In the present work a model of renovascular hypertension was developed in vivo to investigate its usefulness as an antihypertensive drug. AIM OF THE STUDY: Evaluate the effect of acute and 28 day oral administration of G. celosioides extract on systemic arterial pressure and diuresis of renovascular-hypertensive rats, as well as its effect on cardiac remodeling and vascular reactivity. MATERIALS AND METHODS: Ethanolic extract of G. celosioides (EEGC) was used. To induce renovascular hypertension, adult male Wistar rats were submitted to Goldblatt 1K1C or 2K1C surgery. The mean arterial pressure (MAP) of 1K1C animals was directly assessed by cannulation of the carotid artery before and after intraduodenal acute administration of 30, 100 or 300 mg/kg of EEGC. For the 4-week assay, 2K1C animals received daily treatments with water (control group), 100 mg/kg EEGC or 15 mg/kg enalapril for 28 days. Diuresis and caudal blood pressure were assessed weekly, and at the 28th day of treatment, the MAP was directly quantified shortly before euthanasia. Internal organs were removed, weighed and routinely processed for histology and the left ventricle wall was measured. Blood was collected for biochemical analysis and mechanism investigation by quantification of angiotensin converting enzyme (ACE) activity and aldosterone, nitrite and thiobarbituric acid reactive substances (TBARS) concentration. The rats' mesenteric beds were isolated and cannulated to have their pressure variation assessed after crescent doses of phenylephrine (Phe), acetylcholine (ACh) and sodium nitroprusside (SNP). RESULTS: EEGC acutely reduced MAP the dose of 100 mg/kg. In the 4-week assay, EEGC acted as diuretic after acute administration after 1, 2, 3 and 4 weeks of treatment. EEGC also acted as an antihypertensive and it showed significant difference already after 1 week (and after 3 and 4 weeks) compared to control, with its MAP close to pre-surgery values at the end of the experiment. It promoted ACE inhibition, which led to lower aldosterone levels. The lower TBARS and higher nitrite concentration found in the EEGC group suggest antioxidant activity and NO maintenance. Moreover, EEGC counteracted the impairment of vascular reactivity induced by renovascular hypertension. The extract group presented thinner left ventricle wall compared to the control, meaning reduced hypertension-induced cardiac remodeling. CONCLUSIONS: The G. celosioides diuretic effect is maintained on renovascular hypertensive rats and can reduce the blood pressure after the first week of treatment by inhibiting ACE and these effects are longstanding and strong enough to promote protection against cardiac remodeling. Therefore, it shows potential as an antihypertensive drug.

A Unique Case of Renovascular Hypertension due to Fibromuscular Dysplasia in an Extra-renal Artery.

A 33-year-old man was admitted to our hospital to undergo an evaluation to determine the cause of secondary hypertension. Computerized tomography angiography (CTA) showed bilateral multiple renal arteries with significant stenosis of the right extra-renal artery due to fibromuscular dysplasia and segmental impairment of renal perfusion. Although the plasma aldosterone concentration and plasma renin activity were within the normal ranges, percutaneous balloon dilatation of the stenotic lesion resolved his hypertension, leading to a diagnosis of renovascular hypertension caused by segmental renal ischemia due to extra-renal artery stenosis. CTA should be considered during the examination of patients with early-age hypertension, even if the plasma renin activity is not sufficiently elevated.

Renovascular hypertension increases serum TNF and CX3CL1 in experimental Trypanosoma cruzi infection.

Trypanosoma cruzi triggers a progressive inflammatory response affecting cardiovascular functions in humans and experimental models. Angiotensin II, a key effector of the renin-angiotensin system, plays roles in mediating hypertension, heart failure, and inflammatory responses. T. cruzi and AngII can induce inflammatory responses by releasing inflammatory mediators. The aim of this study was to evaluate systemic AngII, tumor necrosis factor (TNF), and CX3CL1 mediators in a two-kidney one-clip (2K1C) renovascular hypertension model using Wistar rats infected with T. cruzi. Our data showed an increase in serum AngII in uninfected and T. cruzi-infected rats 1 week after 2K1C surgery compared to non-2K1C (Sham) animals. The baseline systolic blood pressure was higher in both uninfected and infected 2K1C rats. Despite no difference in circulating parasites in the acute phase of infection, elevated serum TNF and CX3CL1 were observed at 8 weeks post-infection in 2K1C rats in association with higher cardiac inflammatory infiltration. In summary, AngII-induced hypertension associated with T. cruzi infection may act synergistically to increase TNF and CX3CL1 in the 2K1C rat model, thereby intensifying cardiac inflammatory infiltration and worsening the underlying inflammation triggered by this protozoan.

A new low-nephron CKD model with hypertension, progressive decline of renal function, and enhanced inflammation in C57BL/6 mice.

Chronic kidney disease (CKD) is a major health issue in the US. The typical five-sixths nephrectomy (typical 5/6 NX) is a widely used experimental CKD model. However, the typical 5/6 NX model is hypertensive in rats but strain dependent in mice. In particular, C57BL/6 mice with the typical 5/6 NX exhibits normal blood pressure and well-preserved renal function. The goal of the present study was to create a new hypertensive CKD model in C57BL/6 mice. We first characterized the vascular architecture originated from each renal artery branch by confocal laser-scanning microscopy with fluorescent lectin. Then, a novel 5/6 NX-BL model was generated by uninephrectomy combined with 2/3 renal infarction via a ligation of upper renal artery branch on the contralateral kidney. Compared with 5/6 NX-C, the 5/6 NX-BL model exhibited elevated mean arterial pressure (137.6 ± 13.9 vs. 104.7 ± 8.2 mmHg), decreased glomerular filtration rate (82.9 ± 19.2 vs. 125.0 ± 13.9 µl/min) with a reciprocal increase in plasma creatinine (0.31 ± 0.03 vs. 0.19 ± 0.04 mg/dl), and significant renal injury as assessed by proteinuria, histology with light, and transmission electron microscopy. In addition, inflammatory status, as indicated by the level of proinflammatory cytokine TNFα and the leukocyte counts, was significantly upregulated in 5/6 NX-BL compared with the 5/6 NX-C. In summary, we developed a new hypertensive CKD model in C57BL/6 mice with 5/6 renal mass reduction by uninephrectomy and upper renal artery branch ligation on the contralateral kidney. This 5/6 NX-BL model exhibits an infarction zone-dependent hypertension and progressive deterioration of the renal function accompanied by enhanced inflammatory response.

Direct renin inhibition is not enough to prevent reactive oxygen species generation and vascular dysfunction in renovascular hypertension.

Renin-angiotensin system activation promotes oxidative stress and endothelial dysfunction. However, no previous study has examined the effects of the renin inhibitor aliskiren, either alone or combined with angiotensin II type 1 antagonists on alterations induced by two-kidney, one-clip (2K1C) hypertension. We compared the vascular effects of aliskiren (50mg/kg/day), losartan (10mg/kg/day), or both by gavage for 4 weeks in 2K1C and control rats. Treatment with losartan, aliskiren, or both exerted similar antihypertensive effects. Aliskiren lowered plasma Ang I concentrations in sham rats and in hypertensive rats treated with aliskiren or with both drugs. Aliskiren alone or combined with losartan decreased plasma angiotensin II concentrations measured by high performance liquid chromatography, whereas losartan alone had no effects. In contrast, losartan alone or combined with aliskiren abolished hypertension-induced increases in aortic angiotensin II concentrations, whereas aliskiren alone exerted no such effects. While hypertension enhanced aortic oxidative stress assessed by dihydroethidium fluorescence and by lucigenin chemiluminescence, losartan alone or combined with aliskiren, but not aliskiren alone, abolished this alteration. Hypertension impaired aortic relaxation induced by acetylcholine, and losartan alone or combined with aliskiren, but not aliskiren alone, reversed this alteration. Losartan alone or combined with aliskiren, but not aliskiren alone, increased plasma nitrite concentrations in 2K1C rats. These findings show that antihypertensive effects of aliskiren do not prevent hypertension-induced vascular oxidative stress and endothelial dysfunction. These findings contrast those found with losartan and suggest that renin inhibition is not enough to prevent hypertension-induced impaired redox biology and vascular dysfunction.

Renovascular hypertension increases serum TNF and CX3CL1 in experimental Trypanosoma cruzi infection

Trypanosoma cruzi triggers a progressive inflammatory response affecting cardiovascular functions in humans and experimental models. Angiotensin II, a key effector of the renin-angiotensin system, plays roles in mediating hypertension, heart failure, and inflammatory responses. T. cruzi and AngII can induce inflammatory responses by releasing inflammatory mediators. The aim of this study was to evaluate systemic AngII, tumor necrosis factor (TNF), and CX3CL1 mediators in a two-kidney one-clip (2K1C) renovascular hypertension model using Wistar rats infected with T. cruzi. Our data showed an increase in serum AngII in uninfected and T. cruzi-infected rats 1 week after 2K1C surgery compared to non-2K1C (Sham) animals. The baseline systolic blood pressure was higher in both uninfected and infected 2K1C rats. Despite no difference in circulating parasites in the acute phase of infection, elevated serum TNF and CX3CL1 were observed at 8 weeks post-infection in 2K1C rats in association with higher cardiac inflammatory infiltration. In summary, AngII-induced hypertension associated with T. cruzi infection may act synergistically to increase TNF and CX3CL1 in the 2K1C rat model, thereby intensifying cardiac inflammatory infiltration and worsening the underlying inflammation triggered by this protozoan.

Percutaneous Transluminal Angioplasty Improved Posterior Reversible Encephalopathy Syndrome due to Renovascular Hypertension.

A 51-year-old man was admitted to our hospital complaining of preceding throbbing headache and tonic convulsions. Headache and convulsive seizure disappeared and his consciousness recovered to alert within 2 hours after onset. Neurological examination showed no abnormal findings. Laboratory examinations revealed high low-density lipoprotein cholesterol (179 mg/dL), renin (42 ng/mL/hour), aldosterone (265 pg/mL), noradrenaline (1031 pg/mL), and dopamine (79 pg/mL). In brain magnetic resonance imaging (MRI), fluid-attenuated inversion recovery, but not the diffusion-weighted image, showed high signal intensities in white matter in bilateral occipital, parietal, and frontal lobes, with no stenotic changes on magnetic resonance angiography. In addition, the diffusion coefficient of focal lesions was elevated. Decreasing blood flow velocity and separated lumens in the right renal artery trunk were shown by renal artery ultrasonography. Enhanced computed tomography and renal angiography showed right renal partial infarction and isolated stenosis in the right renal artery, accompanied by thrombosed false lumen. No stenotic changes were seen in other peripheral arteries. These findings seemed incompatible with renal dissection and fibromuscular dysplasia, Takayasu's arteritis, and polyarteritis nodosa. Our diagnosis was posterior reversible encephalopathy syndrome (PRES) induced by renal hypertension due to renal artery dissection. To improve the renal artery stenosis and secondary hypertension, we performed plain balloon angioplasty, in addition to administering antihypertensive and lipid-lowering medications. After angioplasty, hypertension and high signal intensity at brain MRI were clearly improved. We would like to emphasize that renal artery angioplasty should be considered as an option for patients with PRES and malignant hypertension.

Attenuation of renovascular hypertension by cyclooxygenase-2 inhibitor partly through ANP release.

Angiotensin II (Ang II) is an important inflammatory mediator. Ang II induces cyclooxygenase-2 (COX-2) expression and prostaglandin F2α release followed by cardiac hypertrophy. Inhibition of COX-2 may modulate high blood pressure but controversy still exists. The aim of this study was to determine the role of COX-2 in the regulation of blood pressure and to define the mechanisms in two kidney one-clip hypertensive (2K1C) rats. Chronic treatment with nimesulide or NS-398 (5 mg/kg/day) for 3 weeks lowered high blood pressure and cardiac hypertrophy with decreased expression levels of cardiac hypertrophy markers [atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP)], Ang type 1 receptor, urotensin II, and urotensin II receptor in 2K1C rats. Plasma level of ANP was markedly increased and plasma levels of Ang II and aldosterone were decreased by treatment with nimesulide or NS-398. In both in vitro and in vivo experiments, nimesulide or NS-398 augmented ANP release in 2K1C rats. The inhibitory effect of NS-398 on blood pressure was attenuated by the pretreatment with natriuretic peptide receptor-A (NPR-A) antagonist (A71915, 30 µg/kg/day). These results suggest that chronic treatment with nimesulide or NS-398 attenuated hypertension and cardiac hypertrophy partly through ANP release in 2K1C rats.

Hydrogen sulfide improves the endothelial dysfunction in renovascular hypertensive rats.

As a novel gasotransmitter, hydrogen sulfide (H(2)S) has vasodilating and antihypertensive effects in cardiovascular system. Thus, we hypothesized that H(2)S might have beneficial effects on thoracic endothelial function in two-kidney one-clip (2K1C) rats, a model of renovascular hypertension. Sodium hydrosulfide (NaHS, 56 micromol/kg/day) was administrated intra-peritoneally from the third day after the 2K1C operation. Along with the development of hypertension, the systolic blood pressure (SBP) was measured before the operation and each week thereafter. The oxidative stress was determined by measurement of malondialdehyde (MDA) concentration, superoxide dismutase (SOD) activity and protein expression of oxidative stress-related proteins (AT(1)R, NADPH oxidase subunits). Acetylcholine (ACh)-induced vasorelaxation and angiotensin II (Ang II)-induced vasocontraction were performed on isolated thoracic aorta. The SBP was significantly increased from the first week after operation, and was lowered by NaHS. NaHS supplementation ameliorated endothelial dysfunction. The protein expression of oxidative stress-related proteins were downregulated, while SOD activity upregulated. In conclusion, improvement of endothelial function is involved in the antihypertensive mechanism of H(2)S. The protective effect of H(2)S is attributable to suppression of vascular oxidative stress that involves inhibition of Ang II-AT(1)R action, downregulation of oxidases, as well as upregulation of antioxidant enzyme.

Azilsartan is associated with increased circulating angiotensin-(1-7) levels and reduced renovascular 20-HETE levels.

BACKGROUND: Activation of angiotensin (ANG) II type 1 receptors (AT1R) promotes vasoconstriction, inflammation, and renal dysfunction. In this study, we addressed the ability of azilsartan (AZL), a new AT1R antagonist, to modulate levels of plasma ANG-(1-7) and renal epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE). METHODS: Sprague-Dawley rats were infused with ANG II (125 ng/min) or vehicle (VEH). AZL (3 mg/kg/day) or VEH was administered starting 1 day prior to ANG II or VEH infusion. On day 10, plasma was obtained for measurement of ANG-(1-7) and kidneys for isolation of microvessels for EET and 20-HETE determination and histological evaluation. RESULTS: Mean 24-hour blood pressure (BP) was not different between VEH and AZL treatment groups, whereas the BP elevation with ANG II infusion (121 ± 5 mm Hg) was completely normalized with AZL cotreatment (86 ± 3 mm Hg). The ANG II-induced renal damage was attenuated and cardiac hypertrophy prevented with AZL cotreatment. Plasma ANG-(1-7) levels (pg/ml) were increased with AZL treatment (219 ± 22) and AZL + ANG II infusion (264 ± 93) compared to VEH controls (74.62 ± 8). AZL treatment increased the ratio of EETs to their dihydroxyeicosatrienoic acid (DHET) metabolites and reduced 20-HETE levels. CONCLUSIONS: Treatment with AZL completely antagonized the elevation of BP induced by ANG II, prevented cardiac hypertrophy, attenuated renal damage, and increased ANG-(1-7) and EET/DHET ratio while diminishing 20-HETE levels. Increased ANG-(1-7) and EETs levels may emerge as novel therapeutic mechanisms contributing to the antihypertensive and antihypertrophic actions of AZL treatment and their relative role compared to AT1R blockade may depend on the etiology of the hypertension.

Biomarkers of kidney injury and klotho in patients with atherosclerotic renovascular disease.

BACKGROUND AND OBJECTIVES: Occlusive renovascular disease and hypertension may progress to CKD. Circulating levels of several biomarkers, including fibroblast growth factor (FGF)-23, Klotho, and soluble urokinase plasminogen activator receptor (suPAR), are altered in patients with CKD, but their role in essential hypertension (EH) and renovascular hypertension (RVH) remains unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Levels of FGF-23, Klotho, suPAR, plasminogen activator inhibitor (PAI)-1, tissue factor, and tissue factor pathway inhibitor (TFI) were measured in the inferior vena cava and renal vein of hypertensive patients with atherosclerotic renal artery stenosis (n=12) or age-matched participants with EH (n=12) and relatively preserved renal function. Single-kidney blood flow was measured to calculate renal release of markers. For control, peripheral vein levels were measured in healthy volunteers (HVs; n=12). RESULTS: FGF-23 levels did not differ among the groups, whereas Klotho levels were lower in participants with RVH and EH than in HVs, and suPAR levels were elevated in patients with RVH compared with HVs and patients with EH (6.1±1.5 versus 4.4±1.9 and 3.2±1.2 ng/ml, P<0.05). PAI-1 levels were higher in patients with RVH than in patients with EH, but tissue factor and TFI levels were not statistically significantly different. After adjustment for GFR, Klotho levels remained decreased in both RVH and EH, and suPAR and PAI-1 levels remained elevated in RVH. eGFR correlated inversely with systemic and renal vein suPAR levels, and directly with systemic Klotho levels. CONCLUSIONS: Klotho levels are low in hypertensive patients, whereas suPAR and PAI-1 levels are specifically elevated in RVH, correlating with GFR. Klotho, PAI-1, and suPAR may be markers of kidney injury in hypertensive patients.

Preserved function of late-outgrowth endothelial cells in medically treated hypertensive patients under well-controlled conditions.

Endothelial progenitor cells (EPCs) participate in renal repair, but their number and function may be impaired by exposure to cardiovascular risk factors. The number of circulating EPCs is decreased in essential and renovascular hypertensive patients, but the effects of hypertension on EPC function are incompletely understood. We hypothesized that EPC function was preserved under well-controlled conditions in treated hypertensive patients. Patients with atherosclerotic renal artery stenosis (ARAS; n=22) or essential hypertension (n=24) were studied during controlled sodium intake and antihypertensive regimen. Late-outgrowth EPCs were isolated from the inferior vena cava (IVC) and renal vein blood of ARAS and essential hypertension patients and a peripheral vein of matched normotensive controls (n=18). The angiogenic function of EPCs was assessed in vitro, and multidetector computed tomography was used to measure single-kidney hemodynamics and function in ARAS and essential hypertension patients. Inflammatory biomarkers and EPC homing signal levels and renal release were calculated. Inferior vena cava and renal vein-obtained EPC function were similar in ARAS and essential hypertension patients and comparable to that in normal controls (tube length, 171.86±16.846, 191.09±14.222, 174.925±19.774 µm, respectively). Function of renal vein-obtained EPCs directly correlated with stenotic kidney glomerular filtration rate, EPC homing factors, and anti-inflammatory mediator levels in ARAS patients. Therefore, EPC function was relatively preserved in ARAS patients, although it directly correlated with renal function. Adequate EPC function supports the feasibility of using autologous EPCs as a therapeutic option in essential and renovascular hypertensive patients. Homing signals and inflammatory mediators may potentially regulate EPC angiogenic function.

Antihypertensive and vascular remodelling effects of the imperatorin derivative OW1 in renovascular hypertension rats.

OW1 is a novel imperatorin derivative that exhibits vasodilator activity. In the present study, the antihypertensive effect of and inhibition of vascular remodelling by OW1 were investigated in two-kidney, one-clip (2K1C) renovascular hypertensive rats. Rats were subjected to the 2K1C procedure and treated with OW1 (40 or 80 mg/kg per day) for 8 weeks. Blood pressure was measured in conscious rats. Microalbumin (mALB) and total protein (U-TP) concentrations were determined in the urine, as were plasma concentrations of angiotensin (Ang) II, calcitonin gene-related peptide (CGRP) and angiotensin-converting enzyme 1 (ACE). The unclipped kidney was stained with haematoxylin and eosin and Masson trichrome, whereas aortic sections were stained with Masson trichrome. In addition, OW1-induced vasodilatation was evaluated in vitro in rat mesenteric and renal arteries. Immunohistochemical analysis was used to quantify collagen I and III expression. OW1 relaxed rat mesenteric and renal arterial rings in vitro. Treatment of 2K1C hypertensive rats with OW1 (40 and 80 mg/kg per day) for 8 weeks significantly decreased blood pressure. In addition, OW1 reduced plasma AngII and ACE concentrations and increased plasma CGRP concentrations. At 80 mg/kg per day, OW1 decreased blood urea nitrogen, mALB and U-TP levels. Histological analysis revealed that OW1 reduced renal arteriolar thickness and relieved the structural hypertrophic arteries. Moreover, OW1 had an inhibitory effect on vascular remodelling and renal lesions in hypertensive rats. In conclusion, the results suggest that OW1 could potentially be a novel candidate for hypertension intervention.