Takashi Uzu

Sodium sensitivity and cardiovascular events in patients with essential hypertension

BACKGROUND In patients with sodium-sensitive hypertension, glomerular pressure is increased and microalbuminuria, a marker of glomerular hypertension, is a predictor of cardiovascular events. Similarly, the lack of a nocturnal decrease in blood pressure in these patients is also associated with an increased risk of cardiovascular events. We hypothesised that sodium sensitivity may be the common factor and carried out a retrospective study of cardiovascular events in patients with essential hypertension who had had sodium sensitivity measured in our clinic. METHODS Sodium sensitivity was assessed in about 350 patients with essential hypertension during the initial investigation of their disorder. The definition of sodium sensitivity was a 10% or greater difference in blood pressure on low-sodium or high-sodium diets. By alphabetical order, the records of 201 patients were obtained and 156 patients without pre-existing disorders were followed up. The records of patients who had a cardiovascular event or died were reviewed without knowledge of the patients sodium-sensitivity status. FINDINGS 62 patients were deemed sodium sensitive and 94 non-sodium sensitive. Left-ventricular hypertrophy was found more frequently in the sodium-sensitive group than in the non-sodium-sensitive group (38 vs 16%; p < 0.01), whereas significantly fewer patients in this group smoked (23 vs 42%; p < 0.05). There were 17 cardiovascular events in the sodium-sensitive group and 14 in the non-sodium-sensitive group. The rate of total, non-fatal and fatal cardiovascular events, was 2.0 per 100 patient-years in the non-sodium-sensitive group and 4.3 per 100 patient-years in the sodium-sensitive group. Coxs proportional-hazards model identified sodium sensitivity (p < 0.01), mean arterial pressure (p < 0.01), and smoking (p < 0.01) as independent cardiovascular risk factors. INTERPRETATION Cardiovascular events occurred more frequently in patients with sodium-sensitive hypertension. Sodium sensitivity is an independent cardiovascular risk factor in Japanese patients with essential hypertension.

Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney

Mitochondrial oxidative damage is a basic mechanism of aging, and multiple studies demonstrate that this process is attenuated by calorie restriction (CR). However, the molecular mechanism that underlies the beneficial effect of CR on mitochondrial dysfunction is unclear. Here, we investigated in mice the mechanisms underlying CR-mediated protection against hypoxia in aged kidney, with a special focus on the role of the NAD-dependent deacetylase sirtuin 1 (Sirt1), which is linked to CR-related longevity in model organisms, on mitochondrial autophagy. Adult-onset and long-term CR in mice promoted increased Sirt1 expression in aged kidney and attenuated hypoxia-associated mitochondrial and renal damage by enhancing BCL2/adenovirus E1B 19-kDa interacting protein 3-dependent (Bnip3-dependent) autophagy. Culture of primary renal proximal tubular cells (PTCs) in serum from CR mice promoted Sirt1-mediated forkhead box O3 (Foxo3) deacetylation. This activity was essential for expression of Bnip3 and p27Kip1 and for subsequent autophagy and cell survival of PTCs under hypoxia. Furthermore, the kidneys of aged Sirt1+/- mice were resistant to CR-mediated improvement in the accumulation of damaged mitochondria under hypoxia. These data highlight the role of the Sirt1-Foxo3 axis in cellular adaptation to hypoxia, delineate a molecular mechanism of the CR-mediated antiaging effect, and could potentially direct the design of new therapies for age- and hypoxia-related tissue damage.

SIRT1 inhibits transforming growth factor beta-induced apoptosis in glomerular mesangial cells via Smad7 deacetylation.

SIRT1, a class III histone deacetylase, is considered a key regulator of cell survival and apoptosis through its interaction with nuclear proteins. In this study, we have examined the likelihood and role of the interaction between SIRT1 and Smad7, which mediates transforming growth factor β (TGFβ)-induced apoptosis in renal glomerular mesangial cells. Immunoprecipitation analysis revealed that SIRT1 directly interacts with the N terminus of Smad7. Furthermore, SIRT1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (Lys-64 and -70) on Smad7. In mesangial cells, the Smad7 expression level was reduced by SIRT1 overexpression and increased by SIRT1 knockdown. SIRT1-mediated deacetylation of Smad7 enhanced Smad ubiquitination regulatory factor 1 (Smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of Smad7 in SIRT1-overexpressing mesangial cells. Stimulation by TGFβ or overexpression of Smad7 induced mesangial cell apoptosis, as assessed by morphological apoptotic changes (nuclear condensation) and biological apoptotic markers (cleavages of caspase3 and poly(ADP-ribose) polymerase). However, TGFβ failed to induce apoptosis in Smad7 knockdown mesangial cells, indicating that Smad7 mainly mediates TGFβ-induced apoptosis of mesangial cells. Finally, SIRT1 overexpression attenuated both Smad7- and TGFβ-induced mesangial cell apoptosis, whereas SIRT1 knockdown enhanced this apoptosis. We have concluded that Smad7 is a new target molecule for SIRT1 and SIRT1 attenuates TGFβ-induced mesangial cell apoptosis through acceleration of Smad7 degradation. Our results suggest that up-regulation of SIRT1 deacetylase activity is a potentially useful therapeutic strategy for prevention of TGFβ-related kidney disease through its effect on cell survival.

Role of Altered Renal Lipid Metabolism in the Development of Renal Injury Induced by a High-Fat Diet

Metabolic syndrome is associated with increased risk of chronic kidney disease, and the renal injury in patients with metabolic syndrome may be a result of altered renal lipid metabolism. We fed wild-type or insulin-sensitive heterozygous peroxisome proliferator-activated receptor gamma-deficient (PPARgamma(+/-)) mice a high-fat diet for 16 weeks. In wild-type mice, this diet induced core features of metabolic syndrome, subsequent renal lipid accumulation, and renal injury including glomerulosclerosis, interstitial fibrosis, and albuminuria. Renal lipogenesis accelerated, determined by increased renal mRNA expression of the lipogenic enzymes fatty acid synthase and acetyl-CoA carboxylase (ACC) and by increased ACC activity. In addition, renal lipolysis was suppressed, determined by reduced mRNA expression of the lipolytic enzyme carnitine palmitoyl acyl-CoA transferase 1 and by reduced activity of AMP-activated protein kinase. In PPARgamma(+/-) mice, renal injury, systemic metabolic abnormalities, renal accumulation of lipids, and the changes in renal lipid metabolism were attenuated. Thus, a high-fat diet leads to an altered balance between renal lipogenesis and lipolysis, subsequent renal accumulation of lipid, and renal injury. We suggest that renal lipid metabolism could serve as a new therapeutic target to prevent chronic kidney disease in patients with metabolic syndrome.

Cardiovascular complications in patients with primary aldosteronism

Primary aldosteronism (PA) is widely believed to be a relatively benign form of hypertension associated with a low incidence of vascular complications. However, several recent studies showed that cardiovascular complications were not rare in PA. PA is known as one of the most typical forms of sodium-sensitive hypertension. Recently, we found that the sodium sensitivity of blood pressure was a marker for greater risk for cardiovascular complications, especially stroke, in patients with essential hypertension. Therefore, we investigated cardiovascular complications in 58 patients with PA confirmed to be Conns adenoma. Cardiovascular complications were found in 34% of 58 patients. Coronary artery disease was found in only one patient (1.7%), as angina pectoris. Stroke was found in nine patients (15.5%), four patients (6.9%) with cerebral infarctions and five patients (8.6%) with cerebral hemorrhages. Proteinuria and renal insufficiency were found in 14 (24.1%) and 4 (6.9%) patients, respectively. The incidence of cerebral infarction and renal insufficiency was greater in men than women. The prevalence of proteinuria was greater in patients with than without stroke (P = 0.03) among those aged older than 40 years. These results indicated that cardiovascular complications, especially stroke and proteinuria, were common in patients with PA, and proteinuria might be an indicator for stroke as target-organ damage.

High Sodium Sensitivity Implicates Nocturnal Hypertension in Essential Hypertension

We investigated the relationship between sodium sensitivity and diurnal variation of blood pressure in patients with essential hypertension. Twenty-eight inpatients with essential hypertension were maintained on high sodium (12 to 15 g NaCl per day) and low sodium (1 to 3 g NaCl per day) diets for 1 week each. Twenty-four-hour blood pressure and urinary sodium excretion were measured at the end of each diet period, and the sodium sensitivity index was calculated as the ratio of the change in mean arterial pressure to the change in urinary sodium excretion rate by sodium restriction. Patients whose average mean arterial pressure was lowered more than 10% by sodium restriction were assigned to the sodium-sensitive group (n = 16); the remaining patients, whose mean arterial pressure was lowered by less than 10%, were assigned to the non-sodium-sensitive group (n = 12). In the non-sodium-sensitive group, mean arterial pressure and heart rate fell during the nighttime, and average values of systolic, diastolic, and mean arterial pressures during the night were significantly lower than those during the day during both low and high sodium diets. On the other hand, in the sodium-sensitive group, there was no nocturnal fall in mean arterial pressure, and none of the systolic, diastolic, and mean arterial pressure values during the nighttime was different from the respective pressure values during the daytime during either sodium diet. The sodium sensitivity index was positively correlated with the fall in mean arterial pressure during the nighttime during a high sodium diet (r = .55, P < .01). These results indicate that in patients with sodium-sensitive essential hypertension, blood pressure fails to fall during the night. High sodium sensitivity may be a marker of greater risk of renal and cardiovascular complications, as has been found in nondippers, patients whose blood pressure fails to fall during the night.

Exendin-4 has an anti-hypertensive effect in salt-sensitive mice model

The improvement of salt-sensitive hypertension is a therapeutic target for various vascular diseases. Glucagon-like peptide 1 (GLP-1), an incretin peptide, has been reported to have natriuretic effect as well as blood glucose lowering effect, although its exact mechanism and clinical usefulness remain unclear. Here, we examined anti-hypertensive effect of exendin-4, a GLP-1 analog, in salt-sensitive obese db/db mice and angiotensin II (angII)-infused C57BLK6/J mice. The treatment of exendin-4 for 12 weeks inhibited the development of hypertension in db/db mice. In db/db mice, the urinary sodium excretion was delayed and blood pressure was elevated in response to a high-salt load, whereas these were attenuated by exendin-4. In db/db mice, intra-renal angII concentration was increased. Furthermore, exendin-4 prevented angII-induced hypertension in non-diabetic mice and inhibited angII-induced phosphorylation of ERK1/2 in cultured renal cells. Considered together, our results indicate that exendin-4 has anti-hypertensive effects through the attenuation of angII-induced high-salt sensitivity.

Prevalence of Renal Artery Stenosis in Autopsy Patients With Stroke

BACKGROUND AND PURPOSE Atherosclerotic renal artery stenosis commonly exists as one manifestation of more generalized atherosclerosis. It is a progressive but potentially curable disorder. Thus, information on renal artery involvement in atherosclerotic diseases could be important. We investigated the prevalence of renal artery stenosis in autopsied patients with stroke over 40 years of age. METHODS From 2167 consecutive autopsy patients who died between 1980 and 1997, we studied 346 cases of mean age of 69+/-11 years with clinical evidence of stroke. RESULTS Atherosclerotic renal artery stenosis (>/=75% luminal area narrowing) was found in 36 patients (10.4%). Patients with renal artery stenosis were older and had worse renal function. Renal artery stenosis was found in 14.7%, 28.6%, and 23.9% of patients with hypertension, renal insufficiency, and aortic aneurysm, respectively. Extracranial carotid artery stenosis (>50% luminal area narrowing) was found in 101 patients (29.2%). Of the 346 stroke patients, 256 had a history of brain infarction. In patients with brain infarction, renal artery stenosis was found in 31 (12.1%) and carotid stenosis was found in 81 (33.6%). Patients with carotid artery stenosis were more likely to have renal artery stenosis than patients without carotid artery stenosis (24.4% versus 5.9%, P<0.0001). Multiple logistic regression analysis identified renal insufficiency, hypertension, female gender, and presence of carotid artery stenosis as independent predictors of renal artery stenosis in patients with brain infarction. CONCLUSIONS These data reveal that atherosclerotic renal artery stenosis is common in patients with stroke, especially in those with brain infarction.

Prevalence and predictors of renal artery stenosis in patients with myocardial infarction

In recent years, the importance of renovascular disease as a cause of end-stage renal disease has been emphasized. Among 1,788 cases autopsied during the 12-year period between 1981 and 1992 at the National Cardiovascular Center Hospital, we examined cases over 40 years of age with autopsy evidence of myocardial infarction to determine the prevalence and predictors of atherosclerotic renal artery stenosis in the atherosclerotic population. Two hundred ninety-seven patients remained for analysis. In this population, atherosclerotic renal artery stenosis was found in 35 patients (12%), and 10 of them had bilateral renal artery stenosis. In patients with hypertension, proteinuria, and renal insufficiency, renal artery stenosis was found in 19%, 39%, and 39%, respectively. As the number of coronary vessels with significant stenosis increased, the prevalence of renal artery stenosis increased. The severity of stenotic lesions of coronary artery was also correlated with the presence of renal artery stenosis. Multiple logistic regression analysis identified age, hypertension, proteinuria, and renal insufficiency as independent predictors of renal artery stenosis. Patients with hypertension, proteinuria, and renal insufficiency had 3.4-, 13.5-, and 4.8-fold increased risk of renal artery stenosis in the population with myocardial infarction. The number of coronary arteries with severe stenosis was also an independent predictor of renal artery stenosis, and had a relative risk of 2.1. These results indicated that atherosclerotic renal artery stenosis is common in patients with myocardial infarction, particularly when hypertension, proteinuria, or renal insufficiency is present. The presence of severe multivessel coronary artery disease suggests a higher incidence of renal artery stenosis.

Reduction in Microalbuminuria as an Integrated Indicator for Renal and Cardiovascular Risk Reduction in Patients With Type 2 Diabetes

OBJECTIVE—Microalbuminuria in diabetic patients is a predictor for diabetic nephropathy and cardiovascular disease. The aim of this study is to investigate the clinical impact of reducing microalbuminuria in type 2 diabetic patients in an observational follow-up study. RESEARCH DESIGN AND METHODS—We enrolled 216 type 2 diabetic patients with microalbuminuria during an initial 2-year evaluation period and observed them for the next 8 years. Remission and a 50% reduction of microalbuminuria were defined as a shift to normoalbuminuria and a reduction <50% from the initial level of microalbuminuria. The association between reducing microalbuminuria and first occurrence of a renal or cardiovascular event and annual decline rate of estimated glomerular filtration rate (eGFR) was evaluated. RESULTS—Twelve events occurred in 93 patients who attained a 50% reduction of microalbuminuria during the follow-up versus 35 events in 123 patients without a 50% reduction. The cumulative incidence rate of events was significantly lower in patients with a 50% reduction. A pooled logistic regression analysis revealed that the adjusted risk for events in subjects after a 50% reduction was 0.41 (95% CI 0.15–0.96). In addition, the annual decline rate of eGFR in patients with a 50% reduction was significantly slower than in those without such a reduction. The same results were also found in the analysis regarding whether remission occurred. CONCLUSIONS—The present study provides clinical evidence implying that a reduction of microalbuminuria in type 2 diabetic patients is an integrated indicator for renal and cardiovascular risk reduction.