Azilsartan causes natriuresis due to its sympatholytic action in kidney disease.

The sympathoinhibitory mechanism of azilsartan was investigated in an adenine-induced chronic renal failure model. Azilsartan exerted an antihypertensive effect, though BP elevation induced by adenine was marginal. The creatinine value was significantly lower in the azilsartan group (AZ) than in the vehicle group (VEH); furthermore, proteinuria was suppressed, and sodium excretion was augmented in the AZ group. The low frequency (LF) of systolic BP was suppressed (VEH: 4.07 ± 2.67 mmHg2 vs. AZ: 3.32 ± 1.93 mmHg2 P < 0.001), and the spontaneous baroreflex gain (sBRG) was augmented (VEH: 1.04 ± 0.62ms/mmHg vs. AZ: 1.38 ± 0.69 ms/mmHg, P < 0.001) in AZ. There were no significant differences in ACE1 and ACE2 expression between the groups, which indicated that the action of azilsartan on these components of the intrarenal renin-angiotensin-aldosterone system was comparatively small. Although NHE3, NKCC, and ENaC expression was similar between the groups, NaCl cotransporter (NCC) expression was markedly suppressed by azilsartan (P < 0.05). Thus, in a mild chronic kidney disease (CKD) model with slight BP elevation, the sympatholytic effect of ARB might be expected, and azilsartan might exert its natriuretic effect by NCC suppression achieved by sympathoinhibitory activity.

DPP-4 inhibition with linagliptin ameliorates the progression of premature aging in klotho-/- mice.

BACKGROUND: The potential of anti-aging effect of DPP-4 inhibitors is unknown. This study was performed to determine whether linagliptin, a DPP-4 inhibitor, could protect against premature aging in klotho-/- mice. METHODS: Klotho-/- mice exhibit multiple phenotypes resembling human premature aging, including extremely shortened life span, cognitive impairment, hippocampal neurodegeneration, hair loss, muscle atrophy, hypoglycemia, etc. To investigate the effect of linagliptin on these aging-related phenotypes, male klotho-/- mice were divided into two groups: (1) control group fed the standard diet, and (2) linagliptin group fed the standard diet containing linagliptin. Treatment with linagliptin was performed for 4 weeks. The effect of linagliptin on the above mentioned aging-related phenotypes was examined. RESULTS: Body weight of klotho-/- mice was greater in linagliptin group than in control group (11.1 ± 0.3 vs 9.9 ± 0.3 g; P < 0.01), which was associated with greater gastrocnemius muscle weight (P < 0.01) and greater kidney weight (P < 0.05) in linagliptin group. Thus, linagliptin significantly prevented body weight loss in klotho-/- mice. Survival rate of klotho-/- mice was greater in linagliptin group (93%) compared to control group (67%), although the difference did not reach statistical significance (P = 0.08). None of linagliptin-treated klotho-/- mice had alopecia during the treatment (P < 0.05 vs control klotho-/- mice). Latency of klotho-/- mice in passive avoidance test was larger in linagliptin group than in control group (P < 0.05), indicating the amelioration of cognitive impairment by linagliptin. Cerebral blood flow of klotho-/- mice was larger in linagliptin group than in control group (P < 0.01), being associated with greater cerebral phospho-eNOS levels (P < 0.05) in linagliptin group. Neuronal cell number in hippocampal CA1 region was greater in linagliptin group than in control group (P < 0.05). Linagliptin group had greater cerebral phospho-Akt (P < 0.05) and phospho-CREB (P < 0.05) than control group. Thus, linagliptin ameliorated brain aging in klotho-/- mice. The degree of hypoglycemia in klotho-/- mice was less in linagliptin group than in control group, as estimated by the findings of OGTT. CONCLUSIONS: Out work provided the evidence that DPP-4 inhibition with linagliptin slowed the progression of premature aging in klotho-/- mice, and provided a novel insight into the potential role of DPP-4 in the mechanism of premature aging.

Detrimental Effects of Centrally Administered Angiotensin II are Enhanced in a Mouse Model of Alzheimer Disease Independently of Blood Pressure.

BACKGROUND: The significance of brain angiotensin II in Alzheimer disease (AD) is unclear. METHODS AND RESULTS: To examine the role of brain angiotensin II in AD, intracerebroventricular angiotensin II infusion was performed on 5XFAD mice, a mouse model of AD, and wild-type mice, and the detrimental effects of brain angiotensin II was compared between the 2 strains of mice. Intracerebroventricular angiotensin II infusion significantly impaired cognitive function in 5XFAD mice but not in wild-type mice. This vulnerability of 5XFAD mice to brain angiotensin II was associated with enhancement of hippocampal inflammation and oxidative stress and with increased cerebrovascular amyloid ß deposition. We also compared the effect of brain angiotensin II on the heart and skeletal muscle between the 2 strains because AD is associated with heart failure and sarcopenia. We found that cardiac compensatory response of 5XFAD mice to brain angiotensin II-induced hypertension was less than that of wild-type mice. Brain angiotensin II caused skeletal muscle atrophy and injury in 5XFAD mice more than in wild-type mice. CONCLUSIONS: Brain angiotensin II seems to be involved in cognitive impairment and brain injury in AD, which is associated with oxidative stress, inflammation, and cerebral amyloid angiopathy. Further, brain angiotensin II may participate in cardiac disease and sarcopenia observed in AD.

High-Fat-Diet Intake Enhances Cerebral Amyloid Angiopathy and Cognitive Impairment in a Mouse Model of Alzheimer's Disease, Independently of Metabolic Disorders.

BACKGROUND: The high-fat Western diet is postulated to be associated with the onset and progression of Alzheimer's disease (AD). However, the role of high-fat-diet consumption in AD pathology is unknown. This study was undertaken to examine the role of high-fat-diet intake in AD. METHODS AND RESULTS: 5XFAD mice, a useful mouse model of AD, and control wild-type mice were fed (1) high-fat diet or (2) control diet for 10 weeks. The effects on cerebral AD pathology, cognitive function, and metabolic parameters were compared between each group of mice. High-fat diet significantly enhanced cerebrovascular ß-amyloid (Aß) deposition (P<0.05) and impaired cognitive function (P<0.05) in 5XFAD mice, but not in wild-type mice. High-fat diet enhanced hippocampal oxidative stress (P<0.05) and NADPH oxidase subunits, gp91(phox) (P<0.01) and p22(phox) (P<0.01) in 5XFAD mice, but not in wild-type mice. Furthermore, high-fat diet reduced cerebral occludin (P<0.05) in 5XFAD mice, but not in wild-type mice. Thus, 5XFAD mice exhibited greater susceptibility to high-fat diet than wild-type mice regarding cerebrovascular injury and cognitive impairment. On the other hand, 5XFAD mice fed high-fat diet exhibited much less increase in body weight, white adipose tissue weight, and adipocyte size than their wild-type counterparts. High-fat diet significantly impaired glucose tolerance in wild-type mice but not in 5XFAD mice. Thus, 5XFAD mice had much less susceptibility to high-fat-diet-induced metabolic disorders than wild-type mice. CONCLUSIONS: High-fat diet, independently of metabolic disorders, significantly promotes the progression of AD-like pathology through enhancement of cerebral amyloid angiopathy and oxidative stress.

Dialysate temperature adjustment as an effective treatment for baroreflex failure syndrome in hemodialysis patient.

BACKGROUND: Baroreflex failure syndrome is a rare disorder which causes labile blood pressure, headache, flushing, diaphoresis and emotional lability. It is caused by history of trauma or radiotherapy in the cervical legion, bilateral carotid-body tumor or resection of glossopharyngeal nerve. We experienced a case of hemodialysis patient who had difficulty in controlling blood pressure during dialysis because of his baroreflex failure syndrome and successfully controlled his blood pressure by adjusting dialysate temperature. CASE PRESENTATION: We report a case of a 68-year-old CKD5 patient who had difficulty in hemodialysis treatment because of severe fluctuations in blood pressure with hypertensive attacks and hypotensive episodes which caused him a severe discomfort. His dialysis treatment was started in 2010 and since that time baroreflex failure syndrome has been suspected because of his clinical manifestations and history of radiotherapy in the cervical region for his lingual cancer in 1994. Baroreflex failure syndrome is diagnosed by symptoms and cold stressor test. We performed a cold stressor test on an experimental baroreflex failure syndrome mouse and induced a significant elevation of blood pressure. From this experimental finding of model mouse, we changed the patients dialysate temperature between 34-38° according to his change in blood pressure though 80-240 mmHg. From this attempt, his blood pressure was successfully controlled between 100-180 mmHg and he was able to continue hemodialysis without any discomfort. CONCLUSION: In our case, environmental stimulation such as temperature change modified the patients fluctuating blood pressure. Change of dialysate temperature could be an option for controlling the unstable blood pressure due to baroreflex failure syndrome.

[Relationship between serum uric acid levels and muscle strength/volume: a new insight from a large-scale survey].

AIM: Serum uric acid (UA) concentration is regulated by its production in the liver and/or intestine and its rate of excretion from the kidneys. However, little is known about skeletal muscle involvement in determining the physiological UA level. The present trial explores whether muscle strength and/or muscle volume is associated with UA levels. MATERIAL & METHODS: Muscle strength was evaluated in terms of grasping power calculated as an average of right and left hand measurements in relation to other parameters in 14,333 subjects (median age; 41.2 years), who were recruited to the study. Skeletal muscle volume was calculated based on the bioimpedance method by subtracting estimated fat volume plus estimated bone weight from the total body weight. RESULTS: 1) Multiple regression analyses to explain the association with UA levels (dependent variable) revealed that BMI, BUN, triglyceride, muscle strength, AST, age and sex are independent variables. 2) Higher UA levels (assessed as 4 UA quartiles) are associated with higher muscle volume, muscle strength, BMI, DBP, and serum creatinine (Cr) concentration. 3) Greater DBP (assessed as 2 UA categories) was associated with higher BMI, muscle strength, muscle volume, UA levels and serum Cr concentration. 4) Regression coefficient "t" for muscle strength was the largest among the other parameters including serum Cr concentration in the UA level ranging from 5.5 to 6.5 mg/dL. CONCLUSION: There was an association between muscle strength/volume and UA levels in the near physiological UA range, suggesting that the circulating UA levels can be, at least in part, controlled by its production in the skeletal muscles.

Estimation of salt intake from spot urine samples in patients with chronic kidney disease.

BACKGROUND: High salt intake in patients with chronic kidney disease (CKD) may cause high blood pressure and increased albuminuria. Although, the estimation of salt intake is essential, there are no easy methods to estimate real salt intake. METHODS: Salt intake was assessed by determining urinary sodium excretion from the collected urine samples. Estimation of salt intake by spot urine was calculated by Tanaka's formula. The correlation between estimated and measured sodium excretion was evaluated by Pearson´s correlation coefficients. Performance of equation was estimated by median bias, interquartile range (IQR), proportion of estimates within 30% deviation of measured sodium excretion (P30) and root mean square error (RMSE).The sensitivity and specificity of estimated against measured sodium excretion were separately assessed by receiver-operating characteristic (ROC) curves. RESULTS: A total of 334 urine samples from 96 patients were examined. Mean age was 58 ± 16 years, and estimated glomerular filtration rate (eGFR) was 53 ± 27 mL/min. Among these patients, 35 had CKD stage 1 or 2, 39 had stage 3, and 22 had stage 4 or 5. Estimated sodium excretion significantly correlated with measured sodium excretion (R = 0.52, P < 0.01). There was apparent correlation in patients with eGFR <30 mL/min (R = 0.60, P < 0.01). Moreover, IQR was lower and P30 was higher in patients with eGFR < 30 mL/min. Estimated sodium excretion had high accuracy to predict measured sodium excretion, especially when the cut-off point was >170 mEq/day (AUC 0.835). CONCLUSIONS: The present study demonstrated that spot urine can be used to estimate sodium excretion, especially in patients with low eGFR.

[Study on the predictors for superimposed preeclampsia in patients with IgA nephropathy].

OBJECTIVE: Pregnancy in chronic kidney disease (CKD) patients is often associated with hypertension and/or the worsening of renal function and neonatal death. The present study explored the clinical characteristics of predictive factors for hypertension in biopsy-proven IgA nephropathy patients with superimposed preeclampsia (SPE). PATIENTS AND METHODS: The subjects were 34 Japanese women with IgA nephropathy whose renal specimen for histological tests was obtained before pregnancy. We retrospectively investigated the relevant clinical factors to explain a rise in blood pressure (BP). The histological findings were evaluated with respect to the quantitative measurements of both global glomerulosclerosis and interstitial damage. RESULTS: Renal biopsies before pregnancies showed that the global glomerular sclerosing index and interstitial damage in the SPE group were significantly higher than in the normal group. The prevalence of SPE was 38.2 % (normal pregnancy 21, SPE 13 cases). The neonatal death rate was 3.0 % (1/34)overall. Just before conception, systolic blood pressure (SBP), serum creatinine (Cr)and blood urea nitrogen (BUN) concentration in the SPE were significantly higher than in normal pregnancies. In contrast, CCr and eGFR were lower in the SPE group than in the normal group. At delivery, serum Cr, BUN and uric acid (UA) concentration in the SPE group were significantly higher than in the normal group. In contrast, CCr and eGFR were lower in the SPE than in the normal group. At delivery, correlation analysis revealed a significant correlation between SBP or diastolic BP (DBP) and the histological severity, between SBP or DBP and daily protein excretion, and between SBP or DBP and serum Cr concentration. With respect to the birth weight of newborns, there was a significant negative correlation between the birth weight and the global glomerular sclerosing rate, and between the birth weight and serum Cr concentration or BUN. A stepwise multiple regression analysis showed that predictive factors for a rise in SBP during pregnancy were the degree of interstitial damage and daily urinary protein excretion. These results suggest that renal function, the magnitude of urinary protein excretion, serum Cr, BUN, UA concentrations, and the severity of histological abnormalities are all associated with SPE occurrence. The predictors of a rise in BP were interstitial damage and urinary protein excretion at pregnancy. In addition, Receiver Operating Characteristic (ROC) analysis showed that both glomerular sclerosis and interstitial damage could be potential predictors for SPE. CONCLUSION: Histological severity in renal biopsy, urinary protein excretion and renal function are associated with SPE in patients with IgA nephropathy. Among these associations, the histological findings and urinary protein excretion may serve as useful predictors for a rise in BP.