Hideyasu Kiyomoto

Tohoku University, Japan

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Publications (109)340.82 Total impact

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    ABSTRACT: In recent times, therapy for renal anemia has changed dramatically in that iron administration has increased and doses of erythropoiesis-stimulating agents (ESAs) have decreased. Here we used a prospective, observational, multicenter design and measured the serum ferritin and hemoglobin levels every 3 months for 2 years in 1086 patients on maintenance hemodialysis therapy. The associations of adverse events with fluctuations in ferritin and hemoglobin levels and ESA and iron doses were measured using a Cox proportional hazards model for time-dependent variables. The risks of cerebrovascular and cardiovascular disease (CCVD), infection, and hospitalization were higher among patients who failed to maintain a target-range hemoglobin level and who exhibited high-amplitude fluctuations in hemoglobin compared with patients who maintained a target-range hemoglobin level. Patients with a higher compared with a lower ferritin level had an elevated risk of CCVD and infectious disease. Moreover, the risk of death was significantly higher among patients with high-amplitude ferritin fluctuations compared with those with a low ferritin level. The risks of CCVD, infection, and hospitalization were significantly higher among patients who were treated with high weekly doses of intravenous iron compared with no intravenous iron. Thus, there is a high risk of death and/or adverse events in patients with hemoglobin levels outside the target range, in those with high-amplitude hemoglobin fluctuations, in those with consistently high serum ferritin levels, and in those with high-amplitude ferritin fluctuations.Kidney International advance online publication, 23 April 2014; doi:10.1038/ki.2014.114.
    Kidney International 04/2014; · 8.52 Impact Factor
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    ABSTRACT: CKD progresses with fibrosis and erythropoietin (Epo)-dependent anemia, leading to increased cardiovascular complications, but the mechanisms linking Epo-dependent anemia and fibrosis remain unclear. Here, we show that the cellular phenotype of renal Epo-producing cells (REPs) alternates between a physiologic Epo-producing state and a pathologic fibrogenic state in response to microenvironmental signals. In a novel mouse model, unilateral ureteral obstruction-induced inflammatory milieu activated NFκB and Smad signaling pathways in REPs, rapidly repressed the Epo-producing potential of REPs, and led to myofibroblast transformation of these cells. Moreover, we developed a unique Cre-based cell-fate tracing method that marked current and/or previous Epo-producing cells and revealed that the majority of myofibroblasts are derived from REPs. Genetic induction of NFκB activity selectively in REPs resulted in myofibroblastic transformation, indicating that NFκB signaling elicits a phenotypic switch. Reversing the unilateral ureteral obstruction-induced inflammatory microenvironment restored the Epo-producing potential and the physiologic phenotype of REPs. This phenotypic reversion was accelerated by anti-inflammatory therapy. These findings demonstrate that REPs possess cellular plasticity, and suggest that the phenotypic transition of REPs to myofibroblasts, modulated by inflammatory molecules, underlies the connection between anemia and renal fibrosis in CKD.
    Journal of the American Society of Nephrology 07/2013; · 8.99 Impact Factor
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    ABSTRACT: OBJECTIVE: Macrophage (Mϕ) migration rests on the adhesion/detachment between Mϕ surface components and extracellular matrixes, and the contribution of numerous inflammatory disorders. Plasminogen activator inhibitor (PAI)-1, a serine protease inhibitor, influences Mϕ motility through an action distinct from its classical modulation of the plasmin-based fibrinolytic process. We rely here on a small molecule PAI-1 inhibitor (TM5275) to investigate the role of PAI-1 in Mϕ migration in the pathogenesis of renal injury.Approach and Results-Mϕ migration was inhibited both in vitro and in vivo by TM5275. It was also reduced in T-cell-deficient nude mice, but not in PAI-1-deficient mice. Mϕ migration hinged on the interaction of PAI-1 with low-density lipoprotein receptor-related protein, an interaction prevented by TM5275, but not with vitronectin, urokinase-type plasminogen activator, or tissue-type plasminogen activator. Fed to rats with anti-Thy-1-induced nephritis, TM5275 significantly decreased Mϕ accumulation and ameliorated the progression of renal injury. CONCLUSIONS: These findings suggest that a small molecule PAI-1 inhibitor represents a novel class of anti-inflammatory agents targeting Mϕ migration by the inhibition of the interaction of PAI-1 with low-density lipoprotein receptor-related protein.
    Arteriosclerosis Thrombosis and Vascular Biology 03/2013; · 6.34 Impact Factor
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    ABSTRACT: The Japan Renal Biopsy Registry (J-RBR) was started in 2007 and the Japan Kidney Disease Registry (J-KDR) was then started in 2009 by the Committee for Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to describe and summarize the registered data from 2009 and 2010. For the J-KDR, data were collected from 4,016 cases, including 3,336 (83.1 %) by the J-RBR and 680 (16.9 %) other cases from 59 centers in 2009, and from 4,681 cases including 4,106 J-RBR cases (87.7 %) and 575 other cases (12.3 %) from 94 centers in 2010, including the affiliate hospitals. In the J-RBR, 3,165 native kidneys (94.9 %) and 171 renal grafts (5.1 %) and 3,869 native kidneys (94.2 %) and 237 renal grafts (5.8 %) were registered in 2009 and 2010, respectively. Patients younger than 20 years of age comprised 12.1 % of the registered cases, and those 65 years and over comprised 24.5 % of the cases with native kidneys in 2009 and 2010. The most common clinical diagnosis was chronic nephritic syndrome (55.4 % and 50.0 % in 2009 and 2010, respectively), followed by nephrotic syndrome (22.4 % and 27.0 %); the most frequent pathological diagnosis as classified by the pathogenesis was IgA nephropathy (31.6 % and 30.4 %), followed by primary glomerular diseases (except IgA nephropathy) (27.2 % and 28.1 %). Among the primary glomerular diseases (except IgA nephropathy) in the patients with nephrotic syndrome, membranous nephropathy was the most common histopathology in 2009 (40.3 %) and minor glomerular abnormalities (50.0 %) were the most common in 2010 in native kidneys in the J-RBR. Five new secondary and longitudinal research studies by the J-KDR were started in 2009 and one was started in 2010.
    Clinical and Experimental Nephrology 02/2013; · 1.25 Impact Factor
  • Hiroshi Okuda, Michiaki Abe, Hideyasu Kiyomoto
    Internal Medicine 01/2013; 52(17):1853. · 0.97 Impact Factor
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    ABSTRACT: The V2 receptor antagonist tolvaptan has been approved for volume control in heart-failure patients in Japan. Tolvaptan increases renal blood flow, and so the present study was designed to ascertain whether tolvaptan could be a useful diuretic for volume control without reducing residual renal function (RRF) in peritoneal dialysis (PD) patients. Tolvaptan was administered in 15 PD patients (15 mg daily). Urine volume, body weight, and blood pressure were monitored Urinary excretion of urea nitrogen Na+, the osmolality of plasma and urine, and peritoneal and renal Kt/V were analyzed before and after tolvaptan treatment. In 11 of 15 patients, urine volume increased to more than 400 mL daily. A significant increase in diluted urine was observed, as indicated by a reduction in the specific gravity or osmolality of urine (or both). Urinary excretion of urea nitrogen, and Na+ was significantly increased Increases in renal Kt/V were observed, but peritoneal Kt/V was unchanged. Singnificant increase in creatinine clearance was also observed These data suggest that tolvaptan not only stimulates water diuresis, but also natriuresis, without reducing RRF in PD patients. Hence, tolvaptan could be a beneficial tool for the control of body fluid and maintenance of RRF in PD patients.
    Advances in peritoneal dialysis. Conference on Peritoneal Dialysis 01/2013; 29:33-7.
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    ABSTRACT: BACKGROUND: Excess fluid distribution is a common disorder in peritoneal dialysis (PD) patients. Tacrolimus malabsorption may also occur in PD patients, and may lead to acute allograft rejection after transplantation. The purpose of this study was to evaluate the relationship between tacrolimus pharmacokinetics and excess fluid distribution according to pre-transplant dialysis modality. METHODS: We retrospectively analyzed 41 adult living-donor kidney transplantations, including nine PD patients and 32 hemodialysis (HD) patients. We examined tacrolimus pharmacokinetics in the peri-operative period and determined the association between the tacrolimus absorption rate and body weight reduction. The absorption efficacy of tacrolimus was evaluated as the dose-normalized tacrolimus absorption rate. Tacrolimus concentrations in PD effluent were measured by high-performance liquid chromatography. RESULTS: The tacrolimus absorption rate on the day before kidney transplantation tended to be lower in PD patients than in HD patients; however, the rate improved after kidney transplantation and was similar in both groups of patients. The peak tacrolimus concentration time was later in PD patients than in HD patients. The body weight reduction after kidney transplantation was greater in PD patients than in HD patients, and was significantly associated with the change in tacrolimus absorption rate (p = 0.04, r = 0.32). Only 0.002 % of the oral tacrolimus dose was removed by PD itself. CONCLUSION: Excess fluid distribution in PD patients appears to contribute to tacrolimus malabsorption rather than PD itself. We should consider the risk of tacrolimus malabsorption in patients with possible excess fluid distribution, particularly in PD patients.
    Clinical and Experimental Nephrology 12/2012; · 1.25 Impact Factor
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    ABSTRACT: BACKGROUND AND OBJECTIVES: Data regarding renal disease in the elderly (age ≥65 years old) and very elderly (age ≥80 years old) Japanese are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in elderly patients who underwent renal biopsy. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: From July 2007 to November 2011, all of the elderly native renal biopsy patients who had been registered in the Japan Renal Biopsy Registry (J-RBR; 2802 including 1596 males and 1206 females) were identified. Their data were compared with a control group of 7416 patients who ranged in age from 20 to 64 years old and were registered on the J-RBR over the same period. In addition, the clinical and pathological classifications of 276 very elderly patients were also analyzed. RESULTS: The indications for biopsy were nephrotic syndrome (NS) in 36.2 and 50.7 % of the elderly and the very elderly patients, chronic nephritic syndrome in 31.8 and 17.4 %, and acute kidney injury including rapidly progressive glomerulonephritis in 18.6 and 22.5 %, respectively. Primary glomerular disease was the most frequent diagnosis, followed by MPO-ANCA-positive nephritis, IgA nephropathy (IgAN), and diabetic nephropathy. In primary GN including IgAN, membranous nephropathy (MN) was the most frequent histological type, followed by IgAN and minor glomerular abnormalities. A comparison with the control group showed that MN, MPO-ANCA-positive nephritis, and amyloid nephropathy were more common in the elderly (P < 0.001), and IgAN was less common (P < 0.001). As for nephrotic syndrome in the elderly, MN was the most common histological type, followed by minimal change NS, diabetic nephropathy, amyloid nephropathy, and focal segmental glomerulosclerosis. There was a significant discrepancy between the urinary protein/creatinine ratio and daily proteinuria after the 7th decade of life. CONCLUSIONS: Renal biopsy is a valuable diagnostic tool, even in elderly and very elderly Japanese patients. In the future, modified clinical guidelines for elderly renal disease should be developed.
    Clinical and Experimental Nephrology 10/2012; · 1.25 Impact Factor
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    ABSTRACT: Donor shortage is a serious problem worldwide and it is now debated whether kidneys from marginal donors are suitable for renal transplantation. Recent studies have shown that the findings of preimplantation kidney biopsy are useful to evaluate vasculopathy in the donated kidney, and may predict transplant outcomes in deceased- donor kidney transplantation. However, few studies have focused on the pathological findings of preimplantation biopsy in living-donor kidney transplantation. Therefore, we investigated whether arteriosclerotic vasculopathy in living-donor kidneys at the time of transplantation predicts the recipient's kidney function (allograft function) later in life. We retrospectively analyzed 75 consecutive adult living-donor kidney transplants performed at Kagawa University Hospital. Renal arteriosclerotic vasculopathy was defined according to the presence of fibrous intimal thickening in the interlobular artery. Forty-one kidneys exhibited mild arteriosclerotic vasculopathy on preimplantation kidney biopsies. The decreases in estimated glomerular filtration rate after donation were similar in donors with or without renal arteriosclerotic vasculopathy. Pre-existing arteriosclerotic vasculopathy did not affect graft survival rate, patient survival rate or the incidence of complications. Recipients of kidneys with arteriosclerotic vasculopathy had lower allograft function at 1 and 3 years after transplantation than the recipients of arteriosclerosis-free kidneys with or without donor hypertension. In multivariate analysis, fibrous intimal thickening on preimplantation biopsy was predictive of reduced allograft function at 1 year after transplantation. The present study demonstrated that mild arteriosclerotic vasculopathy in the donated kidney is an important pathological factor that reflects future impaired function of renal allografts from marginal donors.
    American Journal of Nephrology 07/2012; 36(2):127-35. · 2.62 Impact Factor
  • Nihon Naika Gakkai Zasshi 03/2012; 101(3):759-62.
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    ABSTRACT: Studies were performed to determine if early treatment with an angiotensin II (Ang II) receptor blocker (ARB), olmesartan, prevents the onset of microalbuminuria by attenuating glomerular podocyte injury in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with type 2 diabetes mellitus. OLETF rats were treated with either a vehicle, olmesartan (10 mg/kg/day) or a combination of nonspecific vasodilators (hydralazine 15 mg/kg/day, hydrochlorothiazide 6 mg/kg/day, and reserpine 0.3 mg/kg/day; HHR) from the age of 7-25 weeks. OLETF rats were hypertensive and had microalbuminuria from 9 weeks of age. At 15 weeks, OLETF rats had higher Ang II levels in the kidney, larger glomerular desmin-staining areas (an index of podocyte injury), and lower gene expression of nephrin in juxtamedullary glomeruli, than nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. At 25 weeks, OLETF rats showed overt albuminuria, and higher levels of Ang II in the kidney and larger glomerular desmin-staining areas in superficial and juxtamedullary glomeruli compared to LETO rats. Reductions in mRNA levels of nephrin were also observed in superficial and juxtamedullary glomeruli. Although olmesartan did not affect glucose metabolism, it decreased blood pressure and prevented the renal changes in OLETF rats. HHR treatment also reduced blood pressure, but did not affect the renal parameters. This study demonstrated that podocyte injury occurs in juxtamedullary glomeruli prior to superficial glomeruli in type 2 diabetic rats with microalbuminuria. Early treatment with an ARB may prevent the onset of albuminuria through its protective effects on juxtamedullary glomerular podocytes.
    American Journal of Hypertension 02/2012; 25(5):604-11. · 3.67 Impact Factor
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    ABSTRACT: Reactive renal tubular cells show features of an atypical repair reaction. Differentiation between reactive renal tubular cells and low-grade urothelial carcinoma (LG-UC) cells can therefore be a diagnostic challenge based on morphology alone. In this study, we evaluated the diagnostic utility of vimentin and a high-molecular-weight cytokeratin antibody (clone 34ßE12) in differentiating reactive renal tubular cells from LG-UC. We evaluated voided urine cytology and surgical specimens from 40 patients with renal disease, and 17 patients with LG-UC. All slides were stained with vimentin and 34ßE12. In the reactive renal tubular cells in voided urine cytology, vimentin showed strong cytoplasmic staining in 39/40 (97.5%) cases, but all were negative for 34ßE12. LG-UC cells showed positive staining for 34ßE12 in 3/17 (17.6%) cases, whereas none were positivity for vimentin. The reactive renal tubular cells of histological specimens in the renal disease group demonstrated positive for vimentin in all 40 cases and all were negative for 34ßE12. The LG-UC group showed abnormal staining for 34ßE12 in 4/17 (23.5%) cases, whereas none were positive for vimentin. Vimentin expression in urine cytology can help to distinguish reactive renal tubular cells from LG-UC. However, 34ßE12 does not appear to be a useful adjunct to distinguish these two groups in voided urine cytology.
    Cytopathology 08/2011; 22(4):247-52. · 1.71 Impact Factor
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    ABSTRACT: To clarify the role of angiotensin II (Ang II) in insulin-induced arteriosclerosis, we examined the effects of Ang II on insulin-induced mitogen-activated protein (MAP) kinase activation and cellular hypertrophy in rat vascular smooth muscle cells (VSMCs). Phosphorylated MAP kinases were detected with western blot analysis. Cellular hypertrophy and glucose uptake were evaluated from incorporation of [(3)H]-labeled-leucine and -deoxy-D-glucose, respectively. Cell sizes were measured by Coulter counter. While Ang II (100 nmol/l, 18 h) augmented cellular hypertrophy by insulin (10 nmol/l, 24 h), insulin alone did not affect hypertrophy without Ang II pretreatment. Insulin increased p38MAP kinase and c-Jun N-terminal kinase (JNK) phosphorylation; in the presence of Ang II, p38MAP kinase, and JNK were further activated by insulin. Treatment of a p38MAP kinase inhibitor, SB203580 (10 µmol/l), and a JNK inhibitor, SP600125 (20 µmol/l), abrogated the [(3)H]-leucine incorporation by insulin in the presence of Ang II. Both the Ang II receptor blocker, RNH-6270 (100 nmol/l), and an antioxidant, ebselen (40 µmol/l), inhibited vascular cell hypertrophy. Specific depletion of insulin receptor substrate-1 with small interfering RNA increased [(3)H]-leucine incorporation by insulin (10 nmol/l, 24 h); pretreatment with Ang II attenuated insulin (10 nmol/l, 30 min)-induced glucose uptake. Ang II attenuates insulin-stimulated glucose uptake and enhances vascular cell hypertrophy via oxidative stress- and MAP kinase-mediated pathways in VSMCs. Ang II may also cause insulin signaling to diverge from glucose metabolism into vascular remodeling, affecting insulin-induced arteriosclerosis in hypertension.
    American Journal of Hypertension 06/2011; 24(10):1149-55. · 3.67 Impact Factor
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    ABSTRACT: We demonstrated previously that the blood pressure of patients with IgA nephropathy becomes salt sensitive as renal damage progresses. We also showed that increased urinary angiotensinogen levels in such patients closely correlate with augmented renal tissue angiotensinogen gene expression and angiotensin II levels. Here, we investigated the relationship between urinary angiotensinogen and salt sensitivity of blood pressure in patients with IgA nephropathy. Forty-one patients with IgA nephropathy consumed an ordinary salt diet (12 g/d of NaCl) for 1 week and a low-salt diet (5 g/d of NaCl) for 1 week in random order. The salt-sensitivity index was calculated as the reciprocal of the slope of the pressure-natriuresis curve drawn by linking 2 data points obtained during consumption of each diet. The urinary angiotensinogen:creatinine ratio was significantly higher in patients who consumed the ordinary salt diet compared with the low-salt diet (17.5 μg/g [range: 7.3 to 35.6 μg/g] versus 7.9 μg/g [range: 3.1 to 14.2 μg/g] of creatinine, respectively; P<0.001). The sodium sensitivity index in our patients positively correlated with the glomerulosclerosis score (r=0.43; P=0.008) and changes in logarithmic urinary angiotensinogen:creatinine ratio (r=0.37; P=0.017) but not with changes in urinary protein excretion (r=0.18; P=0.49). In contrast, changes in sodium intake did not alter the urinary angiotensinogen:creatinine ratio in patients with Ménière disease and normal renal function (n=9). These data suggest that the inappropriate augmentation of intrarenal angiotensinogen induced by salt and associated renal damage contribute to the development of salt-sensitive hypertension in patients with IgA nephropathy.
    Hypertension 06/2011; 58(2):205-11. · 6.87 Impact Factor
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    ABSTRACT: We demonstrated previously that the blood pressure of patients with IgA nephropathy becomes salt sensitive as renal damage progresses. We also showed that increased urinary angiotensinogen levels in such patients closely correlate with augmented renal tissue angiotensinogen gene expression and angiotensin II levels. Here, we investigated the relationship between urinary angiotensinogen and salt sensitivity of blood pressure in patients with IgA nephropathy. Forty-one patients with IgA nephropathy consumed an ordinary salt diet (12 g/d of NaCl) for 1 week and a low-salt diet (5 g/d of NaCl) for 1 week in random order. The salt-sensitivity index was calculated as the reciprocal of the slope of the pressure-natriuresis curve drawn by linking 2 data points obtained during consumption of each diet. The urinary angiotensinogen:creatinine ratio was significantly higher in patients who consumed the ordinary salt diet compared with the low-salt diet (17.5 μg/g [range: 7.3 to 35.6 μg/g] versus 7.9 μg/g [range: 3.1 to 14.2 μg/g] of creatinine, respectively; P<0.001). The sodium sensitivity index in our patients positively correlated with the glomerulosclerosis score (r=0.43; P=0.008) and changes in logarithmic urinary angiotensinogen:creatinine ratio (r=0.37; P=0.017) but not with changes in urinary protein excretion (r=0.18; P=0.49). In contrast, changes in sodium intake did not alter the urinary angiotensinogen:creatinine ratio in patients with Ménière disease and normal renal function (n=9). These data suggest that the inappropriate augmentation of intrarenal angiotensinogen induced by salt and associated renal damage contribute to the development of salt-sensitive hypertension in patients with IgA nephropathy.
    Hypertension 06/2011; 58(2):205-11. · 6.87 Impact Factor
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    ABSTRACT: The Committee for the Standardization of Renal Pathological Diagnosis and the Working Group for Renal Biopsy Database of the Japanese Society of Nephrology started the first nationwide, web-based, and prospective registry system, the Japan Renal Biopsy Registry (J-RBR), to record the pathological, clinical, and laboratory data of renal biopsies in 2007. The patient data including age, gender, laboratory data, and clinical and pathological diagnoses were recorded on the web page of the J-RBR, which utilizes the system of the Internet Data and Information Center for Medical Research in the University Hospital Medical Information Network. We analyzed the clinical and pathological diagnoses registered on the J-RBR in 2007 and 2008. Data were collected from 818 patients from 18 centers in 2007 and 1582 patients from 23 centers in 2008, including the affiliated hospitals. Renal biopsies were obtained from 726 native kidneys (88.8%) and 92 renal grafts (11.2%) in 2007, and 1400 native kidneys (88.5%) and 182 renal grafts (11.5%) in 2008. The most common clinical diagnosis was chronic nephritic syndrome (47.4%), followed by nephrotic syndrome (16.8%) and renal transplantation (11.2%) in 2007. A similar frequency of the clinical diagnoses was recognized in 2008. Of the native kidneys, the most frequent pathological diagnosis as classified by pathogenesis was immunoglobulin (Ig) A nephropathy (IgAN) both in 2007 (32.9%) and 2008 (30.2%). Among the primary glomerular diseases (except IgAN), membranous nephropathy (MN) was the most common disease both in 2007 (31.4%) and 2008 (25.7%). In a cross-sectional study, the J-RBR has shown IgAN to be the most common disease in renal biopsies in 2007 and 2008, consistent with previous Japanese studies. MN predominated in the primary glomerular diseases (except for IgAN). The frequency of the disease and the clinical and demographic correlations should be investigated in further analyses by the J-RBR.
    Clinical and Experimental Nephrology 03/2011; 15(4):493-503. · 1.25 Impact Factor
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    ABSTRACT: Aldosterone is well recognized as the selective physiological ligand for mineralocorticoid receptor in epithelia. However, in-vitro studies have demonstrated that the affinity of aldosterone and glucocorticoids for mineralocorticoid receptor is similar. We hypothesized that glucocorticoids are involved in the development of renal injury through an mineralocorticoid receptor-dependent mechanism. Uninephrectomized (UNX) rats were treated with 1% NaCl and divided into three groups: vehicle, bilateral adrenalectomy (ADX) + hydrocortisone (HYDRO; 5 mg/kg/day, s.c.), ADX + HYDRO + eplerenone (0.125% in chow). HYDRO-treated UNX-ADX rats showed increased blood pressure and urinary albumin-to-creatinine ratio with an increase in the expression of the mineralocorticoid receptor target genes, serum and glucocorticoid-regulated kinases-1 and Na+/H+ exchanger isoform-1, in renal tissues. HYDRO treatment induced morphological changes in the kidney, including glomerulosclerosis and podocyte injury. Treatment with eplerenone markedly decreased the gene expression and reduced the albuminuria and renal morphological changes. In contrast, dexamethasone (0.2 mg/kg per day, s.c.) + UNX + ADX induced hypertension and albuminuria in different groups of rats. Eplerenone failed to ameliorate these changes. Our findings indicate that chronic glucocorticoid excess could activate mineralocorticoid receptor and, in turn, induce the development of renal injury.
    Journal of Hypertension 02/2011; 29(2):290-8. · 4.22 Impact Factor
  • Nippon Jinzo Gakkai shi 01/2011; 53(8):1074-138.
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    ABSTRACT: It is widely acknowledged that the (pro)renin receptor mediates angiotensin (Ang) II-dependent and Ang II-independent effects of prorenin. We examined the effect of prorenin on vascular smooth muscle cell (VSMC) signal transduction, proliferation, and hypertrophy. Recombinant rat prorenin dose-dependently increased extracellular signal-regulated kinase (ERK) 1/2 and Akt phosphorylation in rat VSMCs. Prorenin also significantly increased cell number, and [H]-thymidine and [H]-leucine incorporation, which were attenuated by pretreatment with inhibitors for ERK kinase and phosphatidylinositol 3 kinase. Prorenin was also found to stimulate epidermal growth factor (EGF) receptor and Src phosphorylation. Pretreatment of VSMCs with an EGF receptor tyrosine kinase inhibitor and a Src inhibitor significantly attenuated the prorenin-induced increase in ERK 1/2 and Akt phosphorylation, as well as DNA and protein synthesis. Prorenin-induced phosphorylation of the EGF receptor, ERK 1/2, and Akt, as well as DNA and protein synthesis were all blocked by (pro)renin receptor siRNA, but not by an Ang II type 1 receptor blocker, candesartan, nor an Ang-converting enzyme inhibitor, captopril. These results reveal that prorenin directly stimulates VSMC proliferative and hypertrophic changes, dependent on the (pro)renin receptor, independent of Ang II. Furthermore, EGF receptor-mediated ERK 1/2 and Akt activation contributes to prorenin-dependent proliferative and hypertrophic effects in VSMCs.
    Journal of Hypertension 01/2011; 29(4):696-705. · 4.22 Impact Factor
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    ABSTRACT: Drug discovery and development is a lengthy and expensive process. Testing new agents in humans at an early stage could reduce the time and costs involved in identifying drugs that are likely to succeed in clinical studies. New guidance has outlined the concept of exploratory clinical trials, which provide important information on a drug's distribution as well as its physiological and pharmacological effects in humans. This strategy reduces the need for preclinical testing by limiting the dose and duration of exposure to a new drug in humans to below those required by the traditional testing of investigational new drugs. Exploratory, first-in-man studies should provide insights into human physiology and pharmacology, identify therapeutic targets relevant to disease and increase our knowledge of a drug's characteristics. Implementation of a new drug also requires the development of useful biomarkers of disease and of the drug's efficacy, as well as sensitive molecular imaging techniques. In this Review, we outline the benefits of exploratory clinical trials, especially in academia, and provide an overview of the experimental tools necessary for rational drug discovery and development.
    Nature Reviews Nephrology 01/2011; 7(8):469-77. · 7.94 Impact Factor

Publication Stats

2k Citations
340.82 Total Impact Points

Institutions

  • 2010–2013
    • Tohoku University
      • Graduate School of Medicine
      Japan
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
  • 1999–2012
    • Kagawa University
      • • Department of Cardiorenal and Cerebrovascular Medicine
      • • Department of Pharmacology
      • • Faculty of Medicine
      Japan
  • 2011
    • Louisiana State University Health Sciences Center New Orleans
      • Pharmacology
      Baton Rouge, LA, United States
    • Ehime Prefectural University of Health Sciences
      • Department of Medical Technology
      Matuyama, Ehime, Japan
  • 1991
    • Osaka University
      • Department of Internal Medicine
      Ōsaka-shi, Osaka-fu, Japan