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Hypoxia causes proximal tubular cell damage in diabetes, even though proximal tubular cells have an adaptive system to combat hypoxia involving induction of hypoxia factor-1 (HIF-1) and inhibition of mechanistic target of rapamycin complex 1 (mTORC1). Here, we examined the interference effect of altered glucose and lipid metabolism on the hypoxia responses in proximal tubular cells. In culture, hypoxia alone induced HIF-1 and inhibited mTORC1, preventing death in proximal tubular cells. However, hypoxia with high glucose and palmitate increased mTORC1 activity and promoted apoptosis in proximal tubular cells, which was inhibited by pharmacological and genetic inactivation of mTORC1. Since inhibition of all mTORC1’s physiological functions regulated by growth factors including insulin causes various adverse effects, we screened for a microRNA that can inhibit only pro-apoptotic effects of mTORC1 to discover a safe therapeutic target. This screen found microRNA-148b-3p was able to specifically inhibit mTORC1-dependent apoptosis in hypoxic proximal tubular cells exposed to high glucose and palmitate, without affecting insulin-dependent mTORC1 activation. Furthermore, tumor necrosis factor receptor (TNFR) 2 was the target of microRNA-148b-3p and its suppression inhibited apoptosis. Finally, enhanced apoptosis with TNFR2 overexpression was found in hypoxic and mTORC1-activated proximal tubular cells in diabetic rats. Thus, diabetes activated mTORC1 even in hypoxic proximal tubular cells, leading to apoptosis by reducing microRNA-148b-3p expression. Modulating this pathogenic pathway may be a novel therapy for proximal tubular cell damage in diabetes.

Aging is a dominant risk factor for end-stage renal disease. We analyzed the mechanism involved in age-related exacerbation of proteinuria-induced proximal tubular cell (PTC) damage by focusing on endoplasmic reticulum-related unfolded protein response (UPR). After equal-degree induction of proteinuria in 24-month-old (aged) and 3-month-old (young) mice by intraperitoneal free fatty acid-bound albumin overload, tubulointerstitial lesions were more severe in aged than in young mice. In aged PTCs, proteinuria-induced cell-adaptive UPR resulting from induction of the molecular chaperone BiP was significantly suppressed, whereas proapoptotic UPR with CHOP overexpression was enhanced. Treatment with the exogenous molecular chaperone tauroursodeoxycholic acid (TUDCA) ameliorated proteinuria-induced tubulointerstitial lesions and PTC apoptosis in aged mice. Among the three UPR branches, alterations in the inositol-requiring 1α (IRE1α) pathway, but not the activating transcription factor 6 or PERK pathway, were associated with impaired BiP induction in aged kidneys. Moreover, siRNA-mediated suppression of BiP and IRE1α exacerbated free fatty acid–bound albumin-induced apoptosis in cultured PTCs, whereas siRNA-mediated CHOP suppression ameliorated apoptosis. Finally, proteinuria-induced BiP induction in PTCs was diminished in kidney specimens from elderly patients. These results indicate that maladaptive UPRs are involved in proteinuria-induced tubulointerstitial lesions exacerbation in aged kidneys, and that supplementation of chaperones may be used to treat elderly patients with persistent proteinuria. These results should improve understanding of cell vulnerability in aged kidneys.

Aims/Introduction: Although increases in urinary protein excretion generally precede a decline in the glomerular filtration rate, non‐proteinuric renal impairment is common in patients with diabetes. In the present study, we examined the relationship between indices of arterial stiffness and renal function in type 2 diabetic patients without proteinuria.

Aims/Introduction: Platelet-derived microparticles (PDMP) are released from the platelets either after activation or in response to physical stimulation in vivo. The present study examined the association between blood pressure and PDMP, and the effects of high-dose angiotensin receptor blockers (ARB) on PDMP in patients with type 2 diabetes.

The rising incidence of diabetes, metabolic syndrome, and subsequent vascular diseases is now a major public health problem in industrialized countries. New therapeutic strategies to prevent these diseases are urgently needed worldwide. It is well known that calorie restriction (CR) can retard the aging process in organisms ranging from yeast to rodents, and delay the onset of numerous age-related diseases including diabetes. Molecules that mimic CR metabolically are therefore potentially new therapeutic targets for age-related diseases. Silent information regulator 2 (Sir2) is an important player in CR-mediated life span extension. There is also increasing evidence that one of the seven mammalian sirtuins, SIRT1, is involved in regulating cellular processes such as apoptosis. SIRT1 has also been implicated in glucose homeostasis and lipid metabolism in various tissues including adipose tissues, liver, pancreas, and skeletal muscle. This review summarizes current understanding of the biological functions of SIRT1, and discusses its potential as a pharmacological target for fighting metabolic and vascular diseases.

Metabolic syndrome has been reported to be associated with chronic kidney disease, but the mechanisms remain unclear. Although feeding of a high-fat diet (HFD) to C57BL/6 mice is reported to induce systemic metabolic abnormalities and subsequent renal injuries, such as albuminuria, similar to human metabolic syndrome, alterations in HFD-induced renal injuries have not been fully elucidated in detail. We therefore investigated the structural and functional changes in the kidneys of C57BL/6 mice on a HFD. Six-week-old mice were fed a low-fat diet (LFD; 10% of total calories from fat) or a HFD (60% fat) for 12 wk. Mice fed a HFD showed significant increases in body weight, systolic blood pressure, plasma insulin, glucose, and triglycerides compared with those on a LFD. Accompanying these systemic changes, mice on a HFD showed albuminuria, an increase in glomerular tuft area, and mesangial expansion. These systemic and renal alterations in mice on a HFD were prevented by body weight control with the dietary restriction of feeding a HFD. Furthermore, mice on a HFD showed renal pathophysiological alterations including renal lipid accumulation, an increased accumulation of type IV collagen in glomeruli, an increase in macrophage infiltration in the renal medulla, an increase in urinary 8-hydroxy-2′-deoxyguanosine excretion, and impaired sodium handling. In conclusion, this study suggests that local metabolic alterations in the kidney play important roles in the development of renal injury associated with metabolic syndrome in addition to systemic metabolic changes and an increase in body weight.

To assess whether an association between sodium-sensitive hypertension and metabolic syndrome exists; and whether, in patients with metabolic syndrome, the nocturnal fall of blood pressure decreases and salt restriction affects the circadian blood pressure rhythm.

We examined whether thiazide diuretics could restore nocturnal blood pressure (BP) decline and reduce urinary protein excretion in patients with glomerulopathy treated with angiotensin II modulators (angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers).

Recently, we found that the circadian rhythms of natriuresis as well as of glomerular filtration rate were disturbed similar to the blood pressure in non-dipper type of essential hypertension during intake of a high-sodium diet. In this study, we examined circadian rhythms of the urinary albumin excretion rate (AER), which is recognized as a marker of glomerular capillary hydraulic pressure, in addition to those of urinary sodium excretion and blood pressure in 27 patients with essential hypertension. The patients were maintained on relatively high (10–12 g) on low (1–3 g) sodium (NaCl) diets for 1 week. On the last day of each diet, the 24-hour blood pressure was measured every 30 min noninvasively, and during the last 3 days, urine samples were collected for determination of both daytime (07:00–21.30 h) and nighttime (21.30–07.00 h) sodium and AER variations. During the high-sodium diet, nocturnal falls in urinary sodium excretion and blood pressure were observed in dippers (n = 7), while they were not observed in non-dipper (n = 20). The nocturnal decline in AER was also observed in dippers (day: 37 ×/÷ 6 µg/min vs. night: 22 ×/÷ 5 µg/min; p < 0.02), while it was not observed in non-dippers (day: 49 ×/÷ 6 µg/min vs. night: 40 ×/÷ 8 µg/min; NS). During intake of the low-sodium diet, on the other hand, a nocturnal decline in AER was observed in both types of hypertension. Sodium restriction significantly reduced only the nighttime AER in non-dippers (p < 0.01). These findings indicate that changes in dietary sodium intake modified the circadian rhythms of both blood pressure and AER in non-dippers. Renal sodium handling may contribute to determining the circadian rhythm of blood pressure, and furthermore an elevated glomerular capillary hydraulic pressure during the night may enhance the nocturnal albumin excretion in non-dippers.

Hemodialysis (HD) patients have a high rate of cardiac morbidity and mortality. Both symptomatic and silent ischemic heart disease may occur frequently during HD because HD simultaneously reduces coronary artery oxygen delivery while increasing myocardial oxygen demand. The purpose of the present study is to prospectively evaluate the usefulness of a significant ST depression induced by HD for the diagnosis of coronary artery disease (CAD) and as the predictor of subsequent cardiac events in HD patients. Sixty-one patients undergoing chronic HD (50 men, 11 women; mean age, 61 years) admitted for such cardiac symptoms as chest pain (n = 43), arrhythmia (n = 5), or heart failure (n = 13) were studied; 38 patients had CAD by coronary angiography. Electrocardiograms performed during HD showed an additional depression (≥1.0 mV) of the ST segment in 18 patients (positive-ST group), but not in 43 patients (negative-ST group). The incidence of CAD was significantly greater in the former (100%) than in the latter group (46%). A prospective follow-up was performed for 21 ± 2 months, and cardiac events occurred in all positive-ST group patients and in 21 negative-ST group patients. Event-free survival was poorer in the positive-ST group (P< 0.0001). A Cox proportional hazards model identified the significant ST depression as an independent risk factor for cardiac morbidity (P< 0.05), but not for all-cause mortality. ST depression during HD is useful to diagnose CAD in symptomatic patients and is considered an important prognosticator of subsequent cardiac events.

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 Conn's 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.

Abstract: Background. Glomerular mesangial cells were found to have a considerable number of receptors for insulin-like growth factor I (IGF-I) and to proliferate in response to IGF-I. However, the mechanism of the metabolic actions of IGF-I in mesangial cells has not yet been fully elucidated. Methods. In order to clarify the effect of IGF-I on glucose metabolism in mesangial cells, we performed a kinetic analysis of 2-deoxyglucose (2-DOG) uptake, the first step of glucose metabolism, and examined the gene and protein expression of glucose transporter 1 (GLUT 1), a major facilitative glucose transporter in mesangial cells. Results. IGF-I was able to increase 2-DOG uptake significantly after 12 h, and the kinetic analysis of 2-DOG uptake revealed that IGF-I increased maximum velocity (Vmax) without changing Michaelis constant (Km). The expression of GLUT 1 mRNA was increased after the exposure to IGF-I and reached the maximal level at 6 h, followed by an increase in its protein expression. Conclusions. These results suggest that IGF-I plays an important role in glucose metabolism in glomerular mesangial cells by enhancing glucose transport through an increase in the expression of GLUT 1.

We examined the circadian rhythm of urinary sodium excretion and the effects of sodium restriction on rhythm in both dipper and nondipper types of essential hypertension. Patients (n = 26) with essential hypertension were maintained on relatively high- (10 to 12 g/d of sodium chloride) and low-sodium (1 to 3 g/d) diets for 1 week each. On the last day of each diet, 24-hour blood pressures (BPs) were measured every 30 minutes noninvasively with an automatic device, and on the last 3 days, urinary samples were collected for both daytime (7:00 amto 9:30 pm) and nighttime (9:30 pmto 7:00 am). Eight patients were classified as dippers based on a more than 10% reduction in mean arterial pressure (MAP) from daytime to nighttime on a high-sodium diet, and 18 patients were classified as nondippers. A nocturnal decrease in urinary sodium excretion rate (UNaV) on the high-sodium diet was observed in dippers (from 7.5 ± 2.1 during the day to 5.3 ± 2.5 mmol/h at night; P< 0.0001), but not in nondippers (6.7 ± 2.1 v7.6 ± 2.3 mmol/h; not significant). In nondippers, the night-day ratio of sodium excretion was significantly reduced from 1.2 ± 0.4 to 0.8 ± 0.3 (P< 0.003) by sodium restriction; at the same time, the night-day ratio of MAP was reduced from 0.98 ± 0.04 to 0.93 ± 0.05 (P< 0.05). In dippers, the night-day ratios of MAP and UNaV were not affected by sodium restriction, and both ratios remained constant at less than 1. Before sodium restriction, the night-day ratio of sodium excretion correlated with that of MAP (r= 0.78; P< 0.0001), whereas there was no significant correlation (r= –0.05) after sodium restriction. These findings showed that the circadian rhythm of renal sodium excretion differed between the two types of essential hypertension. The enhanced nocturnal natriuresis and diminished nocturnal BP fall on a high-sodium diet, recognized in nondippers, were both normalized by sodium restriction, resulting in circadian rhythms with nocturnal dips in UNaV and BP.

Recently, we found that sodium restriction restored the circadian rhythm of blood pressure from non-dippers to dippers in patients with a sodium-sensitive type of essential hypertension. In the present study, we investigated the effects of sodium restriction on the circadian blood pressure rhythm in patients with primary aldosteronism, a typical sodium-sensitive form of secondary hypertension.

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.

Abstract: We describe 2 patients with autosomal dominant polycystic kidney disease associated with aortic dissection. Both patients presented with chronic renal failure arising from autosomal dominant polycystic kidney disease, as well as with aortic dissection, DeBakey type IIIb.

To assess sodium sensitivity and glomerular haemodynamics in patients with primary aldosteronism.

ABSTRACTAutophagy is essential for the survival of lower organisms under conditions of nutrient depletion. However, whether autophagy plays a physiological role in mammals experiencing starvation is unknown. Ketogenesis is critical for overcoming starvation in mammals. We recently revealed that hepatic and renal autophagy are involved in starvation-induced ketogenesis, by utilizing tissue-specific autophagy-deficient mouse models. The liver is the principal organ to regulate ketogenesis, and a deficiency of liver-specific autophagy partially but significantly attenuates starvation-induced ketogenesis. While deficiency of renal-specific autophagy does not affect starvation-induced ketogenesis, mice with deficiency of both liver and kidney autophagy have even lower blood ketone levels and physical activity under starvation conditions than those lacking autophagy in the liver alone. These results suggest that the kidney can compensate for impaired hepatic ketogenesis. Since ketone bodies are catabolized from fatty acids, the uptake of fatty acids, the formation of intracellular lipid droplets, and fatty acid oxidation are critical for ketogenesis. We found that starvation-induced lipid droplet formation is impaired in autophagy-deficient organs. Thus, hepatic and renal autophagy are required for starvation-induced ketogenesis. This process is essential for maintaining systemic energy homeostasis and physical activity during starvation. Our findings provide a novel insight into mammalian autophagy and the physiology of starvation.

A 21-year-old Japanese male with severe hemophilia A was developed end-stage renal failure. He was placed on combination therapy with peritoneal dialysis (PD) and hemodialysis (HD). Eight months later, he developed a hypertensive cerebral hemorrhage. After emergency surgery, he was managed with PD without HD to avoid cerebral edema. One month later, his renal replacement therapy was switched to HD (three times a week) from PD, since a ventriculoperitoneal shunt catheter was placed to treat his hydrocephalus. HD could be performed safety without anticoagulant agents on condition that factor VIII is given after every HD.

It has been postulated that the lack of nocturnal blood pressure fall in patients called nondippers is associated with more serious end organ damages by hypertension than in dippers whose blood pressure falls during the night. Recently, we found that sodium restriction shifted circadian rhythm of blood pressure from that of a nondipper to a dipper in patients with essential hypertension. In the present study, we aimed to clarify these important findings from the different approaches, and examined which factors affected the diurnal rhythm of blood pressure. A total of 70 patients with essential hypertension were maintained on high and low sodium diets for 1 week each. Nocturnal fall in mean arterial pressure was calculated in each patient, and, based on multiple regression analysis, independent factors affecting this nocturnal fall were examined. Thirty-eight patients were classified as non–sodium-sensitive, whereas 32 were considered sodium sensitive, based on a >10% change in 24-h mean arterial pressure by sodium restriction. In all 70 patients, sodium sensitivity of blood pressure, as well as an interaction between sodium sensitivity and sodium restriction, were identified as independent factors affecting the nocturnal fall. In sodium-sensitive types, in addition to sodium restriction, glomerular filtration rate was identified, whereas, in non–sodium sensitive types, there was no significant factor. Based on multiple regression analysis, the present study reached the same important conclusion as our previous findings: namely, that the enhanced sodium sensitivity was an independent determinant for the diminished nocturnal fall in essential hypertension and that sodium restriction could restore the nocturnal decline, especially in patients with enhanced sodium sensitivity whose nocturnal decline was diminished. Reduced renal sodium excretory capability may be one of the mechanisms involved in nondipping. Am J Hypertens 1999;12:35–39 © 1999 American Journal of Hypertension, Ltd.

The interaction of hypertension with other cardiovascular risk factors, namely hypercholesterolemia, smoking, and past history of cardiovascular complications, was examined. One hundred and ninety-five hemodialysis patients were followed up for 54.2 ± 2.3 months, among whom 66 died. In patients with cardiovascular complications, such as ischemic heart disease, cerebrovascular accident, or atherosclerotic obliteration of peripheral arteries, and in patients older than 70 years, blood pressure had no significant effect on the already poor survival. On the other hand, in patients with hypercholesterolemia (=220 mg/dL) and in smokers, elevated systolic blood pressure made the survival significantly worse. These results suggest an interaction between hypertension and other cardiovascular risk factors in hemodialysis patients. Am J Hypertens 1996;9:1006–1012