Atsushi Yamauchi

Enhanced sodium sensitivity and disturbed circadian rhythm of blood pressure in essential hypertension.

Objective 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. Methods Japanese patients with essential hypertension, who were treated without any antihypertensive agent, were maintained on a high-sodium diet and a low-sodium diet for 1 week each. On the last day of each diet, the 24-h blood pressures were measured. A diagnosis of metabolic syndrome was made according to the International Diabetes Foundation definition Results Among the 56 patients with essential hypertension, 15 patients were complicated with metabolic syndrome while 41 patients were not. The nocturnal blood pressure fall was significant in patients without metabolic syndrome, while it was not so in patients with metabolic syndrome. Only in patients with metabolic syndrome was the nocturnal blood pressure fall enhanced by sodium restriction. The prevalence of sodium-sensitive hypertension in patients with metabolic syndrome was significantly higher than in those without metabolic syndrome (70.6 versus 36.0%, respectively; P = 0.017). A multiple logistic regression analysis revealed central obesity to be an independent risk factor for sodium-sensitive hypertension (odds ratio, 1.41; 95% confidence interval, 1.04–1.91). Conclusions In patients with essential hypertension, an inter-relationship exists among metabolic syndrome, enhanced sodium sensitivity of the blood pressure and non-dipping. The elevated risk of cardiovascular diseases in patients with metabolic syndrome may be related to sodium-sensitive hypertension and non-dipping.

Glucocorticoid-Induced Diabetes Mellitus: Prevalence and Risk Factors in Primary Renal Diseases

Background/Aims: In patients with primary renal diseases the current knowledge of hyperglycemia associated with corticosteroid therapy is limited. We therefore examined the prevalence and risk factors of glucocorticoid-induced diabetes mellitus (DM) in primary renal diseases. Methods: Patients were recruited with primary renal diseases who were started on corticosteroids between April 2002 and June 2005. In patients with DM, an impaired fasting glucose level and/or positive urinary glucose analyses before corticosteroids therapy were excluded. Results: During corticosteroid therapy (initial dose: prednisolone 0.75 ± 0.10 mg/kg/day), DM was newly diagnosed in 17 (40.5%) of 42 patients. All of the 17 patients were diagnosed as having DM by postprandial hyperglycemia at 2 h after lunch, although they had normal fasting blood glucose levels. Age (OR 1.40, 95% CI 1.06–1.84) and body mass index (OR 1.87, 95% CI 1.03–3.38) were determined as independent risk factors for glucocorticoid-induced DM. Conclusion: Over 40% of patients with primary renal disease developed DM during treatment with corticosteroids. A high age and high body mass index are the independent risk factors for glucocorticoid-induced DM. 24-hour urinary glucose analyses and postprandial plasma glucose are useful for detecting glucocorticoid-induced DM.

Localization of rat CLC-K2 chloride channel mRNA in the kidney

To gain insight into the physiological role of a kidney-specific chloride channel, CLC-K2, the exact intrarenal localization was determined by in situ hybridization. In contrast to the inner medullary localization of CLC-K1, the signal of CLC-K2 in our in situ hybridization study was highly evident in the superficial cortex, moderate in the outer medulla, and absent in the inner medulla. To identify the nephron segments where CLC-K2 mRNA was expressed, we performed in situ hybridization of CLC-K2 and immunohistochemistry of marker proteins (Na+/Ca2+ exchanger, Na+-Cl- cotransporter, aquaporin-2 water channel, and Tamm-Horsfall glycoprotein) in sequential sections of a rat kidney. Among the tubules of the superficial cortex, CLC-K2 mRNA was highly expressed in the distal convoluted tubules, connecting tubules, and cortical collecting ducts. The expression of CLC-K2 in the outer and inner medullary collecting ducts was almost absent. In contrast, a moderate signal of CLC-K2 mRNA was observed in the medullary thick ascending limb of Henles loop, but the signal in the cortical thick ascending limb of Henles loop was low. These results clearly demonstrated that CLC-K2 was not colocalized with CLC-K1 and that its localization along the nephron segments was relatively broad compared with that of CLC-K1.To gain insight into the physiological role of a kidney-specific chloride channel, CLC-K2, the exact intrarenal localization was determined by in situ hybridization. In contrast to the inner medullary localization of CLC-K1, the signal of CLC-K2 in our in situ hybridization study was highly evident in the superficial cortex, moderate in the outer medulla, and absent in the inner medulla. To identify the nephron segments where CLC-K2 mRNA was expressed, we performed in situ hybridization of CLC-K2 and immunohistochemistry of marker proteins (Na+/Ca2+exchanger, Na+-Cl-cotransporter, aquaporin-2 water channel, and Tamm-Horsfall glycoprotein) in sequential sections of a rat kidney. Among the tubules of the superficial cortex, CLC-K2 mRNA was highly expressed in the distal convoluted tubules, connecting tubules, and cortical collecting ducts. The expression of CLC-K2 in the outer and inner medullary collecting ducts was almost absent. In contrast, a moderate signal of CLC-K2 mRNA was observed in the medullary thick ascending limb of Henles loop, but the signal in the cortical thick ascending limb of Henles loop was low. These results clearly demonstrated that CLC-K2 was not colocalized with CLC-K1 and that its localization along the nephron segments was relatively broad compared with that of CLC-K1.

Rapid and transient up-regulation of Na+/myo-inositol cotransporter transcription in the brain of acute hypernatremic rats

The osmoregulatory system is well developed in the brain. Osmolytes contribute to maintenance of cell volume and cellular functions without changing intracellular ionic composition. Myo-inositol is regarded as one of the major osmolytes in the brain. In the present study, we investigated the changes in expressions of sodium myo-inositol cotransporter (SMIT) mRNA in the brain of acute hypernatremic rats by in-situ hybridization and Northern blot methods. Under moderate acute hypernatremic conditions, SMIT mRNA level increased markedly at 1 h and returned to almost control levels at 3 h, in accordance with plasma Na+ concentrations. Especially, distinct increases in SMIT mRNA expression were observed in the granule cells and glial cells in the cerebellum. These findings indicate that SMIT plays an important role in osmoregulation, especially in the early stages of acute hypernatremia in the brain.

Developmental regulation of Na+/myo-inositol cotransporter gene expression

Abstract myo -Inositol plays a role in many important aspects of cellular regulation including membrane structure, signal transduction and osmoregulation. It is taken up into the cells by the Na + / myo -inositol cotransporter (SMIT). We investigated developmental changes in the expression of SMIT mRNA and protein in the rat. In the fetal rat brain, SMIT mRNA was abundantly and diffusely expressed throughout the whole brain and the spinal cord. Positive signals were expressed in neuronal and non-neuronal cells in these regions. SMIT is gradually down-regulated nearer birth, but intense signals were still detected in the brain at postnatal day one. In the adult rat brain, very weak hybridization signals were detected throughout whole brain except for the choroid plexus where SMIT mRNA expression remained high. In contrast, the pattern of developmental regulation of SMIT gene expression in the kidney was opposite to that seen in the brain. Signals in the kidney were very weak during embryonic stages, whereas SMIT expression increased significantly after birth. These results suggest that myo -inositol and its transporter play an important role in the CNS developmental stage.

Induction of Na^+/myo-inositol cotransporter mRNA after focal cerebral ischemia : Evidence for extensive osmotic stress in remote areas

Myo-inositol is one of the major organic osmolytes in the brain. It is accumulated into cells through an Na+/myo-inositol cotransporter (SMIT) that is regulated by extracellular tonicity. To investigate the role of SMIT in the brain after cerebral ischemia, we examined expression of SMIT mRNA in the rat brain after middle cerebral artery occlusion, which would reflect alteration of extracellular tonicity. The expression of SMIT mRNA was markedly increased 12 h after surgery in the cortex of the affected side and lasted until the second day. Increased expression was also found in the contralateral cingulate cortex. Up-regulated expression was found predominantly in the neurons in remote areas, although nonneuronal cells adjacent to the ischemic core also expressed this mRNA. These results suggest that cerebral ischemia causes extensive osmotic stress in brain and that the neuronal cells respond to this stress by increasing SMIT expression.

Kainic acid-induced seizure upregulates Na+/myo-inositol cotransporter mRNA in rat brain

A major organic osmolyte, myo-inositol protects cells from perturbing effects of high intracellular concentrations of electrolytes. Myo-inositol is accumulated into cells through Na(+)/myo-inositol cotransporter (SMIT). In order to investigate the regulation of SMIT in generalized seizure, we employed Northern blot analysis and in situ hybridization to study the changes in SMIT mRNA expression in kainic acid-injected rats. Northern blot analysis demonstrated that SMIT mRNA began to increase in the brain 2 h after onset of seizure, and peaked at 12 h. In situ hybridization revealed rapid increase of SMIT mRNA (2 h of seizure) in the CA3 hippocampal pyramidal cells and in the dentate granular cells. Then, at 4-6 h SMIT mRNA expression was observed in the other limbic structure such as amygdala and piriform cortex. Finally, in neocortex and in CA1 pyramidal cells, SMIT mRNA was slowly increased and peaked at 12 h. Microautoradiogram demonstrated that cells expressed SMIT mRNA were mainly neurons. These results suggest that SMIT mRNA is upregulated by kainic acid-induced seizure primarily in structures involved in seizure activity.

Induction of Na+/myo-inositol co-transporter mRNA after rat cryogenic injury

Myo-inositol is one of the major organic osmolytes in the brain. It is stored in the cells by the Na+/myo-inositol co-transporter (SMIT) which is regulated by extracellular osmolality. First, in order to confirm that local change of the osmolality induces alteration of the SMIT mRNA in brain, we examined change of SMIT mRNA of the animals with hypertonic NaCl application to the cortex. Application of hypertonic NaCl up-regulated the SMIT mRNA expression widely surrounding the application site. We next investigated the role of SMIT in brain during vasogenic edema, we examined expression of SMIT mRNA in the rat brain after cryogenic injury. The expression of SMIT mRNA was markedly increased 12 h after surgery and the induction of the mRNA extended to the entire cortex of the affected side. Up-regulated expression was found predominantly in the neurons in remote areas. The induction of SMIT mRNA was found until the 3rd day after surgery. These findings suggest that osmotic stress may spread over a wide area in the cortex in case of vasogenic edema produced by cryogenic injury and that the cells respond to this stress by increasing SMIT expression.

The differential osmoregulation and localization of taurine transporter mRNA and Na+/myo-inositol cotransporter mRNA in rat eyes

We studied the cellular localization and osmotic regulation of taurine transporter (TauT) mRNA in the rat eyes using in situ hybridization. TauT mRNA signals were expressed in the ciliary body, and the outer part of the inner nuclear layer (INL), the outer nuclear layer (ONL) and the inner segment (IS) of the adult rat retina. Chronic hypernatrema, induced by gavaging with 1 ml/100 g body weight of 5% NaCl every other day for 7 days, markedly increased in TauT mRNA in the retina compared with control rats. However, there was little change in TauT mRNA in the eyes in acute hypernatremic state that is induced by single injection of high concentration of NaCl. On the contrary, acute hypernatremic rats displayed markedly elevated Na+/myo-inositol cotransporter (SMIT) mRNA in the retina and the iris-ciliary body and the lens epithelium. Under chronic hypernatremic conditions, there was no significant increase in SMIT mRNA in rat eyes. These findings suggest that TauT mRNA is osmotically regulated in vivo to protect retinal neuronal function, especially against chronic hypernatremic conditions, in contrast to rapid up-regulation of SMIT mRNA in acute hypernatremic rats.

A Young Man with Acute Renal Failure and Severe Loin Pain

The first case of exercise-induced acute renal failure (EIARF) is reported measuring the blood flow and arterial resistance in the kidney by pulsed Doppler ultrasound. A 20-year-old Japanese male suffered from severe loin pain and non-oliguric acute renal failure after strenuous exercise. Serum myoglobin and creatine phosphokinase were normal and urinary myoglobin was not detectable. The Doppler pattern in several segmental arteries showed a slow end-diastolic velocity (EV) and a high resistance index (RI), indicating increased renal vascular resistance, which suggested severe renal vasoconstriction. Three days later, the EV had apparently increased and the RI normalized in accordance with improvement of renal function. The ultrasound Doppler technique is useful for the detection of a decrease in arterial blood flow on real time and for the diagnosis of EIARF.