Shokei Kim-Mitsuyama

The kidney plays a crucial role in blood pressure (BP) regulation by controlling sodium reabsorption along the nephron. NFAT5 (nuclear factor of activated T-cells 5) is a transcription factor that is expressed in various tissues including the kidney and is activated at hypertonic conditions as observed in the renal medulla; the role for kidney NFAT5 in BP regulation, however, remains still obscure. In the present study, we generated inducible and renal tubular cell–specific NFAT5 knockout (KO) mice and characterized their phenotype. The NFAT5 KO mice exhibited high BP, hypernatremia, polyuria, and low urinary sodium excretion without significant alterations in the plasma renin activity or aldosterone concentration. The mice fed a high-salt diet further increased BP, revealing salt-sensitive hypertension. The KO mice ehibited the increased gene expression of the epithelial sodium channel. Protein expression of epithelial sodium channel in the membrane fraction was also significantly increased in KO mice than in wild-type mice. Treatment with amiloride, an epithelial sodium channel blocker, corrected high BP, hypernatremia, and decreased urinary sodium excretion in KO mice to the same levels of those in wild-type mice. Finally, the effects of high-salt diet and amiloride in KO mice were confirmed by the radiotelemetry method. In conclusion, these data indicate that renal tubular NFAT5 should play an important role in regulating sodium reabsorption through epithelial sodium channel under high-salt conditions, thereby preventing salt-dependent hypertension.

To test our hypothesis that the magnitude of reduction in hsCRP achieved by antihypertensive medications may predict the benefit for cardiovascular outcomes in hypertensive individuals, we performed subanalysis of the ATTEMPT-CVD study. The hypertensive participants enrolled in the ATTMEPT-CVD study were categorized into two groups according to whether achieved reduction in hsCRP levels at 6 months after initiation of antihypertensive medications from baseline was equal to or greater than 40% (responder group) or less than 40% (non-responder group). Baseline characteristics and blood pressure during follow-up period were similar between the groups. For women, the incidence of cardiovascular events was significantly less in responder group than non-responder group (P < 0.0221). However, for men, there was no significant difference between the groups regarding incident cardiovascular events (P = 0.2434). There was a significant interaction (P = 0.0187) between sexes for incident cardiovascular events. Our results provide the evidence suggesting that substantial reduction (40% or greater reduction) in hsCRP on antihypertensive medication predicts the benefit for cardiovascular outcomes in hypertensive women but it does not in hypertensive men. The magnitude of achieved reduction in hsCRP by antihypertensive medications seems to be a useful indicator of successful treatment in Japanese hypertensive women.This trial was registered with ClinicalTrials.gov, number NCT01075698.

The predictive value of serum adiponectin for hypertensive cardiovascular outcomes is unknown. This study was performed to investigate the association of adiponectin with incident cardiovascular and renal events (CV events) in hypertensive patients. We performed post-hoc analysis on 1,228 hypertensive patients enrolled in the ATTEMPT-CVD study, a prospective randomized study comparing the effects of two antihypertensive therapies. The participants were divided into quartiles of baseline serum total adiponectin or high molecular weight (HMW) adiponectin. Multivariable Cox proportional hazards analysis was performed to determine the prognostic factors associated with CV events. Kaplan-Meier analysis for CV events by quartiles of baseline total adiponectin showed that patients in the highest total adiponectin quartile (Q4) had more CV events (P = 0.0135). On the other hand, no significant difference was noted regarding the incidence of CV events among patients stratified by HMW adiponectin quartile (P = 0.2551). Even after adjustment for potential confounders, the highest total adiponectin quartile (Q4) remained independently associated with incident CV events in hypertensive patients (HR = 1.949: 95%CI 1.051–3.612; P = 0.0341). These results showed that total adiponectin, but not HMW adiponectin, was independently associated with the incidence of CV events in treated hypertensive patients, thereby highlighting total adiponectin as a valuable predictor for hypertensive cardiovascular outcomes.

Alzheimer’s disease (AD) is increasingly viewed as a neurological disease accompanied by a systemic disorder. Accumulating evidence supports that angiotensin II and angiotensin 1-7 exert opposite effects on various organs including the brain. Howeve

To investigate whether anemia is an independent risk factor for cardiovascular and renal events in hypertensive outpatients, we performed a subgroup analysis of the ATTEMPT-CVD study based on baseline hemoglobin. The ATTEMPT-CVD study was a multicenter, prospective, randomized study of hypertensive outpatients that compared the efficacy of angiotensin receptor blocker (ARB)-based antihypertensive treatment with non-ARB antihypertensive treatment over 3 years. In the present subanalysis, ATTEMPT-CVD study participants (n = 1213) were categorized into the anemic group and nonanemic group according to their baseline hemoglobin. We compared the anemic and nonanemic groups mainly in regard to the incidence of cardiovascular and renal events and blood pressure. We also performed a multivariable Cox proportional hazards analysis to determine the prognostic factors that were independently associated with cardiovascular and renal events. Of the 1213 patients enrolled in the ATTEMPT-CVD, 194 patients had anemia (mostly mild anemia) and 1019 patients did not. Blood pressure was well-controlled during the 3 years of antihypertensive therapy in both the anemic and nonanemic groups. However, the incidence of cardiovascular and renal events was significantly greater in the anemic group than in the nonanemic group (HR = 1.945: 95%CI 1.208–3.130; P = 0.0062). Even after adjustment, anemia was independently associated with cardiovascular and renal events (HR = 1.816: 95%CI 1.116–2.955; P = 0.0163) in overall hypertensive patients with well-controlled blood pressure. Anemia, even mild anemia, is an independent risk factor for cardiovascular and renal events in hypertensive outpatients whose blood pressure is well-controlled. Thus, anemia may be a novel therapeutic target for cardiovascular and renal diseases in hypertensive outpatients with anemia.

The ATTEMPT-CVD study was prospective randomized active-controlled trial and the main findings had been reported. According to baseline GFR and albuminuria categories, we divided the patients of the ATTEMPT-CVD study into 2 subgroups: (Group 1) the patients with at least one of eGFR of 2and UACR of ≥300 mg/g creatinine, defined as G3b and/or A3; (Group 2) the patients except for Group 1, defined as the other patients. In patients with G3b and/or A3, the incidence of cardiovascular events was significantly less in ARB group than in non-ARB group (11 vs 22, respectively) (HR = 0.465: 95%CI = 0.224–0.965; P = 0.040). UACR was significantly less in ARB group than in non-ARB group during follow-up period in patients with G3b and/or A3 (P = 0.0003), while eGFR, plasma BNP levels, and blood pressure were comparable between ARB and non-ARB groups. Allocation to ARB therapy was a significant independent prognostic factor for cardiovascular events in patients with G3b and/or A3 (P = 0.0268). On the other hand, in the other patients, the occurrence of cardiovascular events was comparable between ARB and non-ARB groups. In patients with advanced CKD, ARB-based therapy may confer greater benefit in prevention of cardiovascular events than non-ARB therapy.

To examine the role of ASK1 in Alzheimer’s disease (AD), we generated 5XFAD mice deficient in ASK1 and investigated the characteristics of old 5XFAD and wild-type mice with ASK1 deficiency. ASK1 deficiency improved cognitive function in 24-month-old

Background: The significance of brain angiotensinIIin Alzheimer disease (AD) is unclear.Methods and Results: To examine the role of brain angiotensinIIinAD, intracerebroventricular angiotensinIIinfusion was performed on 5XFADmice, a mouse model ofAD, and wild‐type mice, and the detrimental effects of brain angiotensinIIwas compared between the 2 strains of mice. Intracerebroventricular angiotensinIIinfusion significantly impaired cognitive function in 5XFADmice but not in wild‐type mice. This vulnerability of 5XFADmice to brain angiotensinIIwas associated with enhancement of hippocampal inflammation and oxidative stress and with increased cerebrovascular amyloid β deposition. We also compared the effect of brain angiotensinIIon the heart and skeletal muscle between the 2 strains becauseADis associated with heart failure and sarcopenia. We found that cardiac compensatory response of 5XFADmice to brain angiotensinII–induced hypertension was less than that of wild‐type mice. Brain angiotensinIIcaused skeletal muscle atrophy and injury in 5XFADmice more than in wild‐type mice.Conclusions: Brain angiotensinIIseems to be involved in cognitive impairment and brain injury inAD, which is associated with oxidative stress, inflammation, and cerebral amyloid angiopathy. Further, brain angiotensinIImay participate in cardiac disease and sarcopenia observed inAD.