High-dose Angiotensin Research Articles

Podocyte-Related Mechanisms Underlying Survival Benefit of Long-Term Angiotensin Receptor Blocker.

We previously found that short-term treatment (week 8 to 12 after injury) with high-dose angiotensin receptor blocker (ARB) induced the regression of existing glomerulosclerosis in 5/6 nephrectomy rats. We therefore assessed the effects of long-term intervention with ARB vs. nonspecific antihypertensives in this study. Adult rats underwent 5/6 nephrectomy and renal biopsy 8 weeks later. The rats were then divided into three groups with equivalent renal function and glomerular sclerosis and treated with high-dose losartan (ARB), nonspecific antihypertensive triple-therapy (TRX), or left untreated (Control) until week 30. We found that blood pressure, serum creatinine levels, and glomerulosclerosis were lower at sacrifice in ARB and TRX vs. Control. Only ARB reduced proteinuria and maintained the density of WT-1-positive podocytes. Glomerular tufts showed more double-positive cells for CD44, a marker of activated parietal epithelial cells, and synaptopodin after ARB vs. TRX or Control. ARB treatment reduced aldosterone levels. ARB-treated rats had significantly improved survival when compared with TRX or Control. We conclude that both long-term ARB and triple-therapy ameliorate progression, but do not sustain the regression of glomerulosclerosis. ARB resulted in the superior preservation of podocyte integrity and decreased proteinuria and aldosterone, linked to increased survival in the uremic environment.

Renal outcomes of treatment with telmisartan in patients with stage 3-4 chronic kidney disease: A prospective, randomized, controlled trial (JINNAGA).

Objectives:Although angiotensin II receptor blockers are effective for patients with chronic kidney disease, dose-dependent renoprotective effects of angiotensin II receptor blockers in patients with moderate to severe chronic kidney disease with non-nephrotic proteinuria are not known. Our aim was to elucidate the dose-dependent renoprotective effects of angiotensin II receptor blockers on such patients.Methods:A multicenter, prospective, randomized trial was conducted from 2009 to 2014. Patients with non-nephrotic stage 3–4 chronic kidney disease were randomized for treatment with either 40 or 80 mg telmisartan and were observed for up to 104 weeks. Overall, 32 and 29 patients were allocated to the 40 and 80 mg telmisartan groups, respectively. The composite primary outcome was renal death, doubling of serum creatinine level, transition to stage 5 chronic kidney disease, and death from any cause. Secondary outcomes included the level of urinary proteins and changes in the estimated glomerular filtration rate.Results:There was no difference in the primary outcome (p = 0.78) and eGFR (p = 0.53) between the two groups; however, after 24 weeks, urinary protein level was significantly lower in the 80 mg group than in the 40 mg group (p < 0.05). No severe adverse events occurred in either group, and the occurrence of adverse events did not significantly differ between them (p = 0.56).Conclusion:Our findings do not demonstrate a direct dose-dependent renoprotective effect of telmisartan. The higher telmisartan dose resulted in a decrease in the amount of urinary protein. Even though high-dose angiotensin II receptor blockers may be preferable for patients with stage 3–4 chronic kidney disease, the clinical importance of the study results may be limited. The study was registered in the UMIN-CTR (https://www.umin.ac.jp/ctr) with the registration number UMIN000040875.

ANGIOTENSIN II INDUCES UCP1 IN ADIPOSE TISSUE OF AN EXPERIMENTAL MODEL OF CARDIO-RENAL CACHEXIA

Objective: Cachexia is a severe complication of advanced heart failure and chronic kidney disease. We previously reported that high dose Angiotensin II infusion in rats determined body weight reduction, prevented by an AT-1 receptor blocker treatment and beta-adrenergic non selective antagonism. The possible role of Ang II on UCP1 in white and brown adipose tissue, as a possible mechanism, was investigated in this study. Design and method: Male Sprague-Dawley rats, were implanted subcutaneously in the dorsal region with osmotic minipumps delivering Ang-II at high doses (525 ng/Kg/min) for 12 days to mimic heart failure and the development of cachexia. Five concurrent groups of rats were evaluated: 1) vehicle–infused rats (CTR-rat, n = 9); 2) Ang-II infused rats (n = 7); Ang- II rats receiving by oral gavage 2 days before minipump implantation until the 12th day of Ang-II infusion, either 3) bisoprolol (BIS,β1-adrenergic antagonist, 35 mg/Kg/day, n = 5), or 4) carvedilol (CVD,α1-non-selective-β1,2,3-adrenergic blocker, 90 mg/kg/day, n = 5) or 5) bupranolol (BPR,β3-antagonist, 200 mg/day/kg, n = 4). White adipose tissue (WATs) from retroperitoneal (RWAT), epidydimal (EWAT), dorsal (DWAT) and brown interscapular (IBAT) depot were withdrawn in order to determine UCP1 mRNA expression, norepinephrine tissue level (TNE) and tyrosine hydroxylase activity (THA) Results: THA and TNE were higher in Ang-II infused rats in all the white adipose tissue depots analyzed. CVD prevented TNE increase in all WATs, while BPR and BIS were effective in RWAT and EWAT but not DWAT. All the three beta adrenergic blocker treatments significantly reduced THA increased activity related to Ang-II infusion in all the WATs. UCP1 mRNA was increased in IBAT (+39%, p < 0.05) of Ang II-infused rat, significantly prevented by CVD and BPR but not by BIS. UCP1 was also increased in all the three WATs of Ang-II infused rats, with all the three beta blockers able to reduce the effect in RWAT and DWAT. No effect of beta-blockers treatment was observed in EWAT. Conclusions: High dose angiotensin II infusion determined an increase in UCP1 trascription in brown and white adipose tissue in rats. CVD and BPR were able to prevent UCP1 increase in brown and white adipose tissue more than beta-1 selective antagonist BIS.

DPP-4 Inhibitors as Potential Candidates for Antihypertensive Therapy: Improving Vascular Inflammation and Assisting the Action of Traditional Antihypertensive Drugs.

Dipeptidyl peptidase-4 (DPP-4) is an important protease that is widely expressed on the surface of human cells and plays a key role in immune-regulation, inflammation, oxidative stress, cell adhesion, and apoptosis by targeting different substrates. DPP-4 inhibitors (DPP-4i) are commonly used as hypoglycemic agents. However, in addition to their hypoglycemic effect, DPP-4i have also shown potent activities in the cardiovascular system, particularly in the regulation of blood pressure (BP). Previous studies have shown that the regulatory actions of DPP-4i in controlling BP are complex and that the mechanisms involved include the functional activities of the nerves, kidneys, hormones, blood vessels, and insulin. Recent work has also shown that inflammation is closely associated with the elevation of BP, and that the inhibition of DPP-4 can reduce BP by regulating the function of the immune system, by reducing inflammatory reactions and by improving oxidative stress. In this review, we describe the potential anti-hypertensive effects of DPP-4i and discuss potential new anti-hypertensive therapies. Our analysis indicated that DPP-4i treatment has a mild anti-hypertensive effect as a monotherapy and causes a significant reduction in BP when used in combined treatments. However, the combination of DPP-4i with high-dose angiotensin converting enzyme inhibitors (ACEI) can lead to increased BP. We suggest that DPP-4i improves vascular endothelial function in hypertensive patients by suppressing inflammatory responses and by alleviating oxidative stress. In addition, DPP-4i can also regulate BP by activating the sympathetic nervous system, interfering with the renin angiotensin aldosterone system (RAAS), regulating Na/H2O metabolism, and attenuating insulin resistance (IR).

Multi-Modality Imaging Enables Detailed Hemodynamic Simulations in Dissecting Aneurysms in Mice.

A multi-modality imaging-based modeling approach was used to study complex unsteady hemodynamics and lesion growth in a dissecting abdominal aortic aneurysm model. We combined in vivo ultrasound (geometry and flow) and in vitro optical coherence tomography(OCT) (geometry) to obtain the high resolution needed to construct detailed hemodynamic simulations over large portions of the murine vasculature, which include fine geometric complexities. We illustrate this approach for a spectrum of dissecting abdominal aortic aneurysms induced in male apolipoprotein E-null mice by high-dose angiotensin II infusion. In vivo morphological and hemodynamic data provide information on volumetric lesion growth and changes in blood flow dynamics, respectively, occurring from the day of initial aortic expansion. We validated the associated computational models by comparing results on time-varying outlet flows and vortical structures within the lesions. Three out of four lesions exhibited abrupt formation of thrombus, though different in size. We determined that a lesion without thrombus formed with a thickened vessel wall, which was resolvable by OCT and histology. We attribute differences in final sizes and compositions of these lesions to the different computed flow and vortical structures we obtained in our mouse-specific fluid dynamic models. Differences in morphology and hemodynamics play crucial roles in determining the evolution of dissecting abdominal aortic aneurysms. Coupled high resolution in vivo and in vitro imaging approaches provide much-improved geometric models for hemodynamic simulations. Our imaging-based computational findings suggest a link between perturbations in hemodynamic metrics and aneurysmal disease heterogeneity.

Effects of combination PPARγ agonist and angiotensin receptor blocker on glomerulosclerosis

We previously observed that high-dose angiotensin receptor blocker (ARB) can induce regression of existing glomerulosclerosis. We also found that proliferator-activated recepto-γ (PPARγ) agonist can attenuate glomerulosclerosis in a nondiabetic model of kidney disease, with specific protection of podocytes. We now assessed effects of combination therapy with ARB and pioglitazone on established glomerulosclerosis. Sprague-Dawley male rats underwent 5/6 nephrectomy (5/6 Nx) at week 0 and renal biopsy at week 8. Rats were randomized to groups with equal starting moderate glomerulosclerosis, and treated with ARB, PPARγ agonist (pioglitazone), combination or vehicle from weeks 8 to 12. Body weight, systolic blood pressure (SBP), and urinary protein (UP) were measured at intervals. In rats with established sclerosis, SBP, UP, and GS were equal in all groups at week 8 before treatment by study design. Untreated control rats had hypertension, decreased GFR, and progressive proteinuria and glomerulosclerosis at week 12. Only combination therapy significantly ameliorated hypertension and proteinuria. ARB alone or pioglitazone alone had only numerically lower SBP and UP than vehicle at week 12. Both pioglitazone alone and combination had significantly less decline in GFR than vehicle. Combination-induced regression of glomerulosclerosis in more rats from weeks 8 to 12 than ARB or pioglitazone alone. In parallel, combination treatment reduced plasminogen activator inhibitor-1 expression and macrophage infiltration, and preserved podocytes compared with vehicle. These results were linked to increased AT2 receptor and Mas1 mRNA in the combination group. PPARγ agonists in combination with ARB augment regression of glomerulosclerosis, with downregulation of injurious RAAS components vs PPARγ alone, with increased anti-fibrotic/healing RAAS components, enhanced podocyte preservation, and decreased inflammation and profibrotic mechanisms.

Abstract 13521: Novel Protective Role of Cu Transporter ATP7A Against Cardiac Fibrosis by Inhibiting Endothelial-Mesenchymal Transition Mediated Through Snail and Antioxidant-1

Cardiac fibrosis is attributed to excess pathological deposition of extracellular-matrix (ECM) components; however, it is also mediated through endothelial-mesenchymal transition (EndMT) and fibroblast-myofibroblast transition (FMT) with unknown mechanisms. Copper (Cu), essential micronutrient, has been implicated in fibrosis. Bioavailability of Cu is tightly controlled by Cu-transporter ATP7A which obtains Cu from Cu chaperone Antioxidant-1 (Atox1), and delivers Cu to the ECM secretory Cu enzyme lysysl oxidase (LOX) or exclude Cu. Atox1 also functions as a Cu-dependent transcription factor. However, role of ATP7A in cardiac fibrosis remains unknown. Here we show that high dose angiotensin II infusion (740ng/kg/min for 10 days) to ATP7A mutant (ATP7Amut) mice with reduced Cu transport function significantly increased cardiac fibrosis (200%) and Cu (170%) compared to wild type mice. Blood pressure and heart/body weight were similar between each group. ATP7Amut mice showed increased Isolectin B4+/αSMA+ cells, indicating EndMT in fibrosis region, which was associated with increase in fibrosis-related genes (αSMA, TGFβ1/2/3, CTGF). In ATP7Amut fibroblasts, although LOX activity was reduced, phenotypic conversion to αSMA+ myofibroblasts (FMT) was accelerated. In ECs isolated from ATP7Amut mice or ATP7A-depleted HUVECs, EC phenotype was converted to mesenchymal phenotype with reduced expression of ECs markers (VE-cadherin, VEGFR2) and increased mesenchymal markers (αSMA, TGFβ2) and Cu levels. Functionally, conditioned media from ATP7A-depleted HUVECs promoted cardiac fibroblast differentiation to myofibroblasts (FMT). Mechanistically, ATP7A knockdown in ECs increased expression of EndMT master regulatory transcription factor Snail as well as Atox1 (2 fold). Atox1 overexpression by adenovirus increased EndMT-inducing genes (αSMA, TGFβ2, Hey2) via binding to their promoters at Atox1 binding sites (GAAAGA) without affecting EC markers or Snail which is shown to reduce EC markers. In summary, ATP7A limits cardiac fibrosis by inhibiting EndMT and FMT via suppressing transcription factors Snail and Atox1. Thus, ATP7A is a potential therapeutic target for fibrosis-dependent cardiovascular diseases.

HLA-G expression of cervical reserve cell-like cells regenerated from human induced pluripotent stem (iPS) cells and its relationship with cervical cancer stem cells in immune escape

s / Journal of Reproductive Immunology 112 (2015) 121–140 125 pregnant mice. During pregnancy in mice, continuous infusion of high-dose angiotensin II (AngII) induced hypertension, proteinuria, and IUGR, whereas infusion of low-dose AngII caused hypertension alone. AngII-induced hypertension was prevented in Nlrp3−/− mice but not in Asc−/−, indicating that NLRP3 contributes to gestational hypertension independently of ASC-mediated inflammasomes. Although NLRP3 deficiency had no effect on IUGR, it restored IL-6 upregulation in the placenta and kidney of AngIIinfused mice. These findings demonstrate that NLRP3 contributes to the development of gestational hypertension independently of the inflammasomes. http://dx.doi.org/10.1016/j.jri.2015.09.016

NLRP3 Deficiency Improves Angiotensin II-Induced Hypertension But Not Fetal Growth Restriction During Pregnancy.

Preeclampsia is a pregnancy-specific syndrome characterized by elevated blood pressure, proteinuria, and intrauterine growth restriction (IUGR). Although sterile inflammation appears to be involved, its pathogenesis remains unclear. Recent evidence indicates that sterile inflammation is mediated through the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes, composed of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1. Here we investigated the role of the NLRP3 inflammasomes in the pathogenesis of preeclampsia using Nlrp3(-/-) and Asc(-/-) (Nlrp3 and Asc deficient) pregnant mice. During pregnancy in mice, continuous infusion of high-dose angiotensin II (AngII) induced hypertension, proteinuria, and IUGR, whereas infusion of low-dose AngII caused hypertension alone. AngII-induced hypertension was prevented in Nlrp3(-/-) mice but not in Asc(-/-), indicating that NLRP3 contributes to gestational hypertension independently of ASC-mediated inflammasomes. Although NLRP3 deficiency had no effect on IUGR, it restored the IL-6 up-regulation in the placenta and kidney of AngII-infused mice. Furthermore, treatment with hydralazine prevented the development of gestational hypertension but not IUGR or IL-6 expression in the placenta and kidney. These findings demonstrate that NLRP3 contributes to the development of gestational hypertension independently of the inflammasomes and that IUGR and kidney injury can occur independent of blood pressure elevation during pregnancy.

Reactive oxygen species partially mediate high dose angiotensin II-induced positive inotropic effect in cat ventricular myocytes.

Reactive oxygen species, such as superoxide, are being increasingly recognized as key components of a vast array of signaling pathways. Angiotensin II is a well-recognized stimulus for superoxide production through NADPH oxidase activation and opening of the mitochondrial ATP-sensitive potassium channels (mKATP). A role for this mechanism has been proposed to explain several physiological effects of the peptide. The aim of this study was to evaluate the involvement of this mechanism in the inotropic response to 100nmol/L angiotensin II. Sarcomere shortening and intracellular pH (BCECF-epifluorescence technique) were evaluated in isolated cat ventricular myocytes placed in a perfusion chamber on the stage of an inverted microscope. Myocardial superoxide production was evaluated by the lucigenin quimioluminiscence method. Angiotensin II (100nmol/L) increased~70% sarcomere shortening, effect that was only partially prevented by NADPH oxidase inhibition, mKATP channel blockade or inhibition of the cardiac Na(+)/H(+) exchanger (NHE-1). Moreover, angiotensin II stimulates NHE-1 activity by a NADPH oxidase-dependent mechanism. Myocardial superoxide production was also increased by angiotensin II, and this action was completely prevented either by NADPH oxidase inhibition or mKATP channel blockade. The positive inotropic response to 100nmol/L angiotensin II is due to both ROS/NHE-1 dependent and independent pathways, this being a point of divergence with the signaling previously described to be triggered by lower concentrations of angiotensin II (i.e.: 1nmol/L).

Fibrosis and renal aging

Glomerulosclerosis and interstitial fibrosis increase in the aging kidney, and glomerular filtration rate (GFR) decreases with increasing age. Decreases in stem cell number and function contribute to renal aging. High-dose angiotensin receptor blocker (ARB) not only slows the progression of glomerular and vascular sclerosis in aging but can also induce regression of these processes independently of its hemodynamic actions. By using new interventions, such as peroxisome proliferator activator receptor gamma (PPARγ) agonist, we can manipulate the process of renal aging by regulating stem cells and other mechanisms.

Serelaxin reduces oxidative stress and asymmetric dimethylarginine in angiotensin II-induced hypertension

Recent findings suggest the therapeutic action of relaxin during hypertension is dependent on nitric oxide synthase (NOS) activation; however, the mechanisms underlying the beneficial effects of relaxin on the NOS system have not been fully elucidated. We hypothesized that the protective effects of relaxin include reducing both oxidative stress and the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). We examined the effect of Serelaxin [human recombinant relaxin-2 (RLX)] in male Sprague-Dawley rats given high-dose angiotensin (ANG) II (400 ng·kg(-1)·min(-1) sc) for 6 wk or shams. RLX was administered (4 μg/h sc) to half of the rats in each group after 2 wk of ANG II for the remaining 4 wk. ANG II induced hypertension and proteinuria, reduced NO oxidation products (NOx), and increased oxidative stress (NADPH oxidase activity, thiobarbituric acid-reactive substances, and 8-isoprostane excretion) and plasma ADMA. While RLX had no effect on sham rats, RLX attenuated the ANG II-dependent hypertension (165 ± 5 vs. 135 ± 13 mmHg, P < 0.05) and proteinuria at 6 wk (62 ± 6 vs. 41 ± 4 mg·day(-1)·100 g(-1), P < 0.05) and normalized oxidative stress and circulating ADMA, in association with restored NOx excretion and kidney cortex NOx. We found that RLX had no impact on the ADMA-regulatory enzymes protein arginine methyltransferase and dimethylarginine-dimethylaminohydrolase (DDAH). Furthermore, RLX treatment did not increase DDAH activity in kidney cortex or liver. These data suggest that benefits of RLX treatment include reduced ADMA levels and increased NO bioavailability, possibly due to its antioxidant effects.

Abstract 472: Effect of Different Doses of Angiotensin II Receptor Blockers on Adipokine Levels in Hypertensive Patients

The present study was designed to determine the effect of different doses of the angiotensin II receptor blocker, candesartan, on circulating adiponectin and leptin levels as well as plasma leptin adiponectin ratio (LAR) in hypertensive patients with multiple cardiovascular risk factors. 69 hypertensive patients were randomized to 3 groups: group 1 included patients treated with high doses of Candesartan (32mg), group 2 included patients treated with conventional doses of Candesartan (16mg), group 3 included patients that received antihypertensive treatment other that ARBs or ACEIs. Patients were evaluated for lipid profile, HbA1C, insulin, C-peptide, CRP, aldosterone, renin,HOMA-IR, leptin , adiponectin and LAR. Baseline adiponectin, leptin and LAR levels did not differ significantly between the three groups. After six months of treatment LAR was significantly higher in group 3 than group 1 (p=0.007) or group 2 (p=0.023). Marginal across-group differences were detected for post-treatment circulating adiponectin level (p=0.064). Univariate GLM analysis of posttreatment LAR detected significant by-group differences even after adjustment for age, sex, baseline values of LAR and blood pressure. In this model, group was the only significant predictor of LAR after controlling for these variables. Treatment with high doses of angiotensin II receptor blocker, candesartan, is associated with significantly reduced LAR and marginally increased circulating adiponectin levels in hypertensive patients with multiple cardiovascular risk factors.

Sex differences in response to angiotensin II receptor blocker-based therapy in elderly, high-risk, hypertensive Japanese patients: a subanalysis of the OSCAR study

The OlmeSartan Calcium Antagonists Randomized (OSCAR) study is a multicenter, prospective, randomized, open-label, blinded, end point study of elderly hypertensive Japanese patients that compared the efficacy of a high-dose angiotensin II receptor blocker (ARB) treatment to an ARB plus calcium channel blocker (CCB) combination. In this pre-specified subgroup analysis, we compared the response to such therapy according to sex. A total of 1164 patients (515 (44%) men and 649 (56%) women) were included, and each gender was split into two nearly equal treatment groups. The primary end point was a composite of cardiovascular events and non-cardiovascular death. The baseline characteristics between the two treatment groups in each sex were similar, except for some variables. Male patients had lower systolic and higher diastolic blood pressure than female patients (156.8/85.7 vs. 158.5/84.2 mm Hg). At the end of the study, the mean systolic pressure was higher in the ARB group (134.4 mm Hg) than in the ARB plus CCB group (131.5 mm Hg; P=0.03) for men but not for women (135.4 vs. 133.4 mm Hg; P=0.12). For men, the primary outcome events tended to be higher in the ARB group than in the ARB plus CCB group (hazard ratio (HR)=1.66; P=0.055) but not for women (HR=0.97; P=0.92). This difference in men was due to cardiovascular events (HR=1.86; P=0.03). The interaction between sex and treatment group was not significant (P=0.17). These findings suggest that, in addition to blood pressure control, appropriate patient risk assessment is important for the treatment of hypertension, especially in male patients, as opposed to possible sex differences in treatment effects.

Genomics and Disease Progression in IgA Nephritis

Apart from clinical, histological and biochemical indices, genomics are now being employed to unravel the pathogenetic mechanisms in the disease progression of IgA nephritis (IgAN). The results of angiotensin converting enzyme (ACE) gene polymorphism have been controversial. Those patients with the DD genotype seem to have a poorer prognosis. However, with high dose angiotensin receptor blocker (ARB) therapy, the ACE gene polymorphism status of a patient may no longer be a matter for concern as those with the DD genotype would also respond favourably to high dose ARB therapy. Association studies with gene sequencing and haplotypes have suggested that multiple genes are involved in the pathogenesis of IgAN. Some workers have reported a synergistic effect in the combined analysis of AGT-M235T and ACE I/D polymorphism. With the use of deoxyribo nucleic acid (DNA) microarray, tens of thousands of gene expressions genome-wide can be examined together simultaneously. A locus of familial IgAN has been described with strong evidence of linkage to IgAN1 on chromosome 6q22-23. Two other loci were reported at 4q26-31 and 17q12-22. DNA microarray techniques could also help in the identification of specific pathogenic genes that are up- or down-regulated and this may allow genome wide analyses of these genes and their role in the pathogenesis and progression of IgAN. Recently, using genome-wide association studies (GWAS) more loci for disease susceptibility for IgAN have been identified at 17p13, 8p23, 22q12, 1q32 and 6p21.

A retrospective Aliskiren and Losartan study in non-diabetic chronic kidney disease.

To assess the efficacy of combined Aliskiren and Losartan vs high dose Losartan and Aliskiren alone in chronic kidney disease (CKD). This is a retrospective study of 143 patients with non-diabetic CKD comparing combined Aliskiren (150 mg/d) with Losartan (100 mg/d) therapy vs High dose Angiotensin receptor blockers (ARB) (Losartan 200 mg/d) and the third group Aliskiren (150 mg/d) alone. This study involved only patient medical records. Entry criteria included those patients who had been treated with the above drugs for at least 36 mo within the 5 years period; other criteria included proteinuria of 1 g or more and or CKD Stage 3 at the start of the 36 mo period. The study utilised primary renal end points of estimated Glomerular Filtration Rate (eGFR) < 15 mL/min or end stage renal failure. Patients treated with high dose ARB compared to the other two treatment groups had significantly less proteinuria at the end of 36 mo (P < 0.007). All 3 groups had significant reduction of proteinuria (P < 0.043, P < 0.001). Total urinary protein was significantly different between the 3 groups over the 3-year study period (P = 0.008), but not eGFR. The changes in eGFR from baseline to each year were not significantly different between the 3 therapeutic groups (P < 0.119). There were no significant differences in the systolic and diastolic blood pressure between the 3 drug groups throughout the 3 years. The incidence of hyperkalemia (> 5.5 mmol/L) was 14.2% (7/49) in the Combined Aliskiren and ARB group, 8.7% (4/46) in the Aliskiren alone group and 6.3% (3/48) in the High dose ARB group (P < 0.001). This study in non-diabetic CKD patients showed that Combination therapy with Aliskiren and ARB was effective but was not safe as it was associated with a high prevalence of hyperkalaemia.

Feasibility of Regression of Hypertension Using Contemporary Antihypertensive Agents

Recently, we reported that transient treatment of genetically hypertensive rats with high-dose angiotensin receptor blocker (ARB) causes regression of established hypertension. In this study, we investigated whether treatment with candesartan or nifedipine controlled-release (CR) resulted in a sustained regression of hypertension in humans. Patients aged 30 to 59 years with untreated stage 1 essential hypertension and a family history of hypertension were treated with the antihypertensive agents candesartan (n = 124) or nifedipine CR (n = 120). After 1 year of treatment (phase 1), the medications were tapered and discontinued (phase 2). During phase 2, home and office blood pressures were monitored for another year to assess posttreatment reoccurrence of stage 1 hypertension. In phase 1, after 1 year of treatment a similarly substantial BP decrease was seen in the candesartan (-24.5/16.1 mm Hg) and nifedipine (-26.8/18.0 mm Hg) groups. In phase 2 there was a substantial reoccurrence of hypertension; at the study end, only 1 patient was able to continue without antihypertensive medication. However, a Kaplan-Meier analysis revealed a significant delay of reoccurrence of hyper tension (P = 0.0001) in the candesartan group. One year of treatment with candesartan or nifedipine CR was not associated with marked regression of hypertension in humans at the standard doses used in this trial. However, withdrawal of candesartan was associated with a slightly longer delay before restarting medications. Further studies with larger doses of candesartan given over a longer time are required to determine whether such a regimen may induce sustainable and clinically relevant reversal of hypertension and alteration in its natural history.

The role of central memory CD8 T cells in the kidney and the role of these cells in genesis of hypertension

Immunological memory is an important function of the adaptive immunity in response to pathogenic stimuli. Effector memory T cells, which are CD44 high CD62L low, reside in various non‐lymphoid tissues and serve as a first line defense against foreign antigens. We have previously shown that T cells are important in hypertension, but the role of memory T cells has not been defined. Here, we show that hypertension also causes immunological memory. The presences of CD8+/ CD62Lhi/CC44hi, CCR7hi central memory‐like cells in the kidney are increased 5 to 10‐fold compared to sham infused mice. Moreover, the central memory CD8 T cells produce IFN‐r and up‐regulate IL‐18R. To examine a potential role of these cells in hypertension, we re‐infused a low dose of angiotensin II that minimally raises blood pressure in naïve mice (200 ng/kg/min) 4 weeks after stopping an initial infusion of either high dose angiotensin II or vehicle. This low‐dose angiotensin II increased blood pressure to 137±6mmHg in the animals that had previously received a vehicle infusion, but to 172±12mmHg in mice that had received angiotensin II. Thus, these studies show that hypertension is associated with the development of central memory CD8+ T cells and that these cells may promote a severe hypertensive response to subsequent exposure to angiotensin II. This memory model allows us to investigate the role of memory CD8 T cells in genesis of hypertension.

An angiotensin II receptor blocker–calcium channel blocker combination prevents cardiovascular events in elderly high-risk hypertensive patients with chronic kidney disease better than high-dose angiotensin II receptor blockade alone

The OSCAR study was a multicenter, prospective randomized open-label blinded end-point study of 1164 Japanese elderly hypertensive patients comparing the efficacy of angiotensin II receptor blocker (ARB) uptitration to an ARB plus calcium channel blocker (CCB) combination. In this prospective study, we performed prespecified subgroup analysis according to baseline estimated glomerular filtration rate (eGFR) with chronic kidney disease (CKD) defined as an eGFR <60 ml/min per 1.73 m2. Blood pressure was lower in the combined therapy than in the high-dose ARB cohort in both groups with and without CKD. In patients with CKD, significantly more primary events (a composite of cardiovascular events and noncardiovascular death) occurred in the high-dose ARB group than in the combination group (30 vs. 16, respectively, hazard ratio 2.25). Significantly more cerebrovascular and more heart failure events occurred in the high-dose ARB group than in the combination group. In patients without CKD, however, the incidence of primary events was similar between the two treatments. The treatment-by-subgroup interaction was significant. Allocation to the high-dose ARB was a significant independent prognostic factor for primary events in patients with CKD. Thus, the ARB plus CCB combination conferred greater benefit in prevention of cardiovascular events in patients with CKD compared with high-dose ARB alone. Our findings provide new insight into the antihypertensive strategy for elderly hypertensive patients with CKD.

Losartan/hydrochlorothiazide combination therapy surpasses high-dose angiotensin receptor blocker in the reduction of morning home blood pressure in patients with morning hypertension.

Angiotensin receptor blockers (ARBs) are the first-line antihypertensive agents. In clinical practice, it is often difficult to achieve the recommended blood pressure level by ARBs in their ordinal dosages alone. This study examined the practical efficacy of a combination therapy of ARB with thiazide diuretics for lowering morning home blood pressure (MHBP) in comparison to high-dose ARB therapy in patients with morning hypertension administered an ordinal dosage of ARB. This study was performed in a prospective, randomized, open-labeled and blind-endpoint fashion. Patients were considered to have morning hypertension when their self-measured systolic MHBPs were 135mmHg or higher, irrespective of their diastolic MHBP and office blood pressures (OBPs). Forty-eight outpatients with morning hypertension receiving the ordinal dosage of ARB were given either losartan/hydrochlorothiazide (n = 26) or high-dose ARB (n = 22) in place of their previously prescribed ARB. No change in any medication was permitted during this period. Decreases of both systolic and diastolic MHBP after 3 months of treatment were significantly greater in the losartan/hydrochlorothiazide group than in the high-dose ARB group (p < 0.05, respectively). The ratio of adverse events was somewhat high (23.1% in the losartan/hydrochlorothiazide group, 9.1% in the high-dose ARB group, respectively). However, there were no significant differences in any particular adverse event between groups. This study suggested losartan/hydrochlorothiazide might be superior to high-dose ARB for reducing morning home blood pressure.