Hypertension: Yamaguchi Y

Yamaguchi Y. · Department of Pathology, Kashiwa Hospital, Jikei University · Nippon Rinsho. · Pubmed #16523935 No free full text.

This publication has no abstract.

Ichida K, Yamaguchi Y, Matsumura T. · Division of Nephrology & Hypertension, Department of Internal Medicine, Jikei University School of Medicine. · Nippon Rinsho. · Pubmed #12629699 No free full text.

This publication has no abstract.

Yamaguchi Y, Takahashi S. · Third Department of Internal Medicine, Kyorin University School of Medicine. · Nippon Rinsho. · Pubmed #12187747 No free full text.

Abstract: Esophagogastroduonenoscopy(EGD) is a useful tool not only for diagnostic examination but also for less invasive treatment. However, it is the well-known fact that complications occur during EGD, particularly in elderly patients. We reviewed EGD performed for elderly patients. Arrhythmia, elevated blood pressure over 50 mmHg, increased the pulse rates and decreased of oxygen saturation during EGD were more common in elderly patients. Changes in these parameters occurred more frequently when EGD passed through the pharynx at the time of insertion. In conclusion, EGD for elderly patients should be performed more gently and carefully, particularly at the time of insertion.

Miura S, Yamaguchi Y, Urata H, Himeshima Y, Otsuka N, Tomita S, Yamatsu K, Nishida S, Saku K. · Department of Cardiology, Fukuoka University School of Medicine, Japan. · Hypertens Res. · Pubmed #15824468 links to  free full text

Abstract: With conventional lifestyle modification programs, it can be difficult for hypertensive individuals to modify their lifestyles and maintain the changes. We assessed whether a multicomponent program (patient-centered assessment and counseling for exercise plus nutrition [PACE+ Japan]) based on behavior theory and social cognitive theory would be effective for treating patients with essential hypertension. We examined 57 outpatients aged 62+/-10 years with essential hypertension irrespective of antihypertensive drug treatment. Participants were randomly divided into two groups: 1) a PACE+ Japan follow-up group (n =18), who were given an action-plan sheet and systemic health counseling by a physician and counselor every 4 weeks for 24 weeks, and 2) a PACE+ Japan-only group (n =20), who were given an action-plan sheet but did not receive counseling. An age- and sex-matched control group (n =19) was also selected. The decrease in systolic blood pressure (SBP) (Delta SBP=SBP at 24 weeks minus that at 0 weeks) in the PACE+ Japan follow-up group was significantly greater than that in the control group. In addition, the Delta percentage of Fat (%Fat) and Delta urinary sodium extraction (U-Na) in the PACE+ Japan follow-up group were significantly greater than those in the control group. With regard to changes in total energy expenditure, exercise energy expenditure and total energy intake between 0 weeks and 24 weeks, significant improvements were observed for the PACE+ Japan follow-up group. Delta U-Na was determined to significantly predict Delta SBP as assessed by stepwise selection. In addition, the partial correlation coefficient of Delta SBP with Delta U-Na was 0.361 (p =0.011) as assessed by a multiple regression analysis. Therefore, PACE+ Japan follow-up counseling was associated with a reduction in SBP, which in turn was associated with reduction in U-Na. This new program may be effective for reducing blood pressure in hypertensives.

Matsuo N, Yamamoto H, Kobayashi A, Yamamoto I, Mitome J, Maruyama Y, Hayakawa H, Miyazaki Y, Utsunomiya Y, Hosoya T, Yamaguchi Y. · Division of Kidney and Hypertension, Department of Internal Medicine, Kashiwa Hospital, The Jikei University School of Medicine, Chiba, Japan. · Clin Transplant. · Pubmed #19594591 No free full text.

Abstract: A 59-yr-old Japanese woman with chronic renal failure caused by IgA nephropathy and antineutrophil cytoplasmic antibody (ANCA)-related glomerulonephritis underwent kidney transplantation from a living unrelated spousal donor. The blood type was compatible, while the human leukocyte antigen (HLA) typing showed a 5/6 locus mismatch. She had become pregnant twice by her donor and had never received blood transfusions. Complement-dependent cytotoxicity cross-match, flow cytometry cross-match (FCXM), and flow panel reactive antibody (PRA) were negative. She initially underwent one week of immunosuppression with mycophenolate mofetil (MMF) and double filtration plasmapheresis (DFPP) immediately before transplantation to reduce the risk of antibody-mediated rejection. Induction therapy consisted of MMF, tacrolimus (TAC), methylprednisolone (MP), and basiliximab. The allograft function was excellent immediately after the operation. However, the urine output and platelet count declined rapidly on post-operative day (POD) 3, while the serum creatinine (sCr) and lactate dehydrogenase levels rose gradually. Subsequently, we could not detect the diastolic arterial flow on Doppler sonography. We diagnosed accelerated acute rejection and treated her with plasma exchange (PEX), intravenous MP pulse therapy, and rituximab. The first episode biopsy on POD 7 revealed acute vascular rejection and acute antibody-mediated rejection (Banff score AMR II). Her urinary excretion increased beginning on POD 13, while the sCr level decreased gradually and reached 0.9 mg/dL on POD 22. In our retrospective analysis, the LAB screen detected donor-specific antibody (DSA). This case suggested that, for successful kidney transplantation in highly sensitized recipients, such as husband-to-wife spousal kidney transplantation with a history of pregnancy, we should keep the risk of AMR in mind, even if the sensitive antibody detection tests are negative.

Ohno I, Yamaguchi Y, Saikawa H, Uetake D, Hikita M, Okabe H, Ichida K, Hosoya T. · Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo. · Intern Med. · Pubmed #19293539 links to  free full text

Abstract: BACKGROUND: Sevelamer, a nonabsorbed hydrogel that binds phosphate, is reported to reduce the serum urate concentration in maintenance hemodialysis patients, however the urate-lowering mechanism remains obscure. In this study we verify the urate-lowering effect of sevelamer in Japan in which the hemodialysis environment is different from that of western countries, and we also clarify the urate-lowering mechanism of sevelamer. METHODS: A total of 127 Japanese patients undergoing maintenance hemodialysis were investigated. These patients consisted of 93 males and 34 females, and their mean age was 58.4+/-12.4 years (range, 25-88 years). The mean duration of hemodialysis was 8.7+/-6.1 years (range, 0.5-27.5 years). Sevelamer was added to each patient's former prescription for the treatment of hyperphosphatemia, and the changes in laboratory data before and after administration of sevelamer were compared. In order to clarify the mechanism of urate-lowering effect by sevelamer, a urate adsorption experiment was carried out in vitro. RESULTS: Sevelamer significantly decreased serum phosphate value three and six months after administration. Sevelamer showed a significant reduction in serum urate values in maintenance hemodialysis patients with hyperuricemia, but not in patients with normouricemia. The change rate of serum urate correlated with the change rate of serum phosphate and the change rate of serum calcium x phosphate product, but did not correlate with that of serum calcium. Sevelamer hydrochloride adsorbed urate in vitro. CONCLUSION: Sevelamer decreases serum urate possibly by adsorbing urate in hemodialysis patients.

Yamamoto I, Horita S, Takahashi T, Kobayashi A, Toki D, Tanabe K, Hattori M, Teraoka S, Aita K, Nagata M, Yamaguchi Y. · Division of Kidney and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan. · Am J Transplant. · Pubmed #19032226 No free full text.

Abstract: Peritubular capillary basement membrane multilayering (PTCBMML) is a pathological landmark of chronic rejection-induced transplant capillaropathy (TC), but its cellular mechanisms are not fully understood. We observed de novo caveolae formation in endothelial cells in TC under electron microscopy. To examine the role of caveolae and their structural components in TC, biopsy samples from cases of chronic rejection were double-immunostained for Caveolin-1 (Cav-1) and Pathologische Anatomie Leiden-endothelium (PAL-E; a marker of peritubular capillary [PC]). Thirty-two cases of chronic rejection (group I) were compared with 18 cases of interstitial fibrosis and tubular atrophy with no evidence of any specific etiology (IF/TA; group II) and eight cases of peritubular capillaritis (group III). The Cav-1/PAL-E immunoreactivities in groups I-III (%Cav-1/PAL-E) were 41.8+/-23.1%, 8.1+/-7.3% (p < 0.01 vs. group I) and 12.7+/-7.4% (p < 0.01 vs. group I), respectively. Furthermore, multiple linear regression models demonstrated that %Cav-1/PAL-E was independently associated with the PTCBMML grade and reduced PC number. No correlation was observed between %Cav-1/PAL-E and PC C4d deposition in group I. We conclude that de novo caveolae formation in PC endothelia is involved in TC in chronic rejection.

Ohno I, Okabe H, Yamaguchi Y, Saikawa H, Uetake D, Hikita M, Gomi H, Ichida K, Hosoya T. · Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. · Nippon Jinzo Gakkai Shi. · Pubmed #18546882 No free full text.

Abstract: A study was conducted to determine whether combination treatment using allopurinol and benzbromarone was more useful than single allopurinol treatment for the gout and hyperuricemia accompanying renal dysfunction. The subjects were 45 male patients who received urate-lowering treatment and showed a stable serum urate level. The patients were divided into four groups according to the urate-lowering treatment and creatinine clearance (Ccr) (A group: single treatment, normofunction, B group: single treatment, hypofunction, C group: combined treatment, normofunction, D group: combined treatment, hypofunction). There were no differences in serum urate levels among the four groups. Urate clearance (CUA)and daily urinary urate excretion (UUAV) showed significantly high values in the C group, but no difference was seen in the fractional excretion of urate (FEUA) among the four groups. The dosage of allopurinol in the D group was significantly lower than in the A and B groups. Serum oxypurinol concentration in the C group was lower than that in the B group. Oxypurinol clearance (C oxypurinol) in the C group was significantly high compared with the B and D groups. There was a close correlation between C oxypurinol, Ccr, and CUA, with an especially strong correlation between C oxypurinol and CUA. There were no differences in the serum concentration and clearance of xanthine and hypoxanthine among the four groups. Results of the study suggested that combination treatment using allopurinol and benzbromarone for the gout and hyperuricemia accompanying renal dysfunction is more useful, because a lower dose of allopurinol can be used and the serum oxypurinol concentration is reduced compared with single allopurinol treatment.

Hoshi S, Yamaguchi Y, Sanaka T, Hosoya T. · Tokyo Women's Medical University Medical Center East, Tokyo, Japan. · Nippon Jinzo Gakkai Shi. · Pubmed #18546880 No free full text.

Abstract: BACKGROUND: Although pathological changes in the vascular lesions of malignant nephrosclerosis have been quantified, little is understood about interstitial changes. We quantified pathological changes such as glomerular damage (glomerular sclerosis and collapse), vascular patency and interstitial fibrosis to determine statistical correlations with clinical data. METHODS: We examined 25 patients who were diagnosed with malignant hypertension and investigated correlations among age, urinary protein, SUN, 1/Cre, systolic BP and diastolic BP (from medical charts), interstitial fibrosis, glomerular damage, acute tubular damage (semiquantified by scoring) and arterial and arteriolar patency (from renal biopsies). RESULTS: Interstitial fibrosis inversely correlated with 1/Cre (p=0.0114), interlobular arterial patency (p= 0.0139) and total vascular patency (p = 0.0499). Glomerular damage tended to correlate with urinary protein, but the values did not reach the level of statistical significance (p=0.0666). On the other hand, glomerular damage correlated with neither interstitial fibrosis nor vascular patency. Acute tubular damage closely correlated with both diastolic (p= 0.0086) and systolic (p = 0.0075) BP. CONCLUSIONS: Interstitial damage increases with decreasing interlobular arterial patency and renal function decreases with increasing interstitial damage. Since acute tubular damage that can progress to chronic interstitial damage closely correlates with BP, the control of BP might indirectly influence the prognosis of renal function.

Kunitomo M, Yamaguchi Y, Kagota S, Otsubo K. · School of Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Hyogo, Japan. · J Pharmacol Sci. · Pubmed #18544898 links to  free full text

Abstract: Metabolic syndrome (MetS) is a group of cardiovascular risk factors, including visceral obesity, glucose intolerance, hypertension, and dyslipidemia. Increased oxidative and nitrative stress and inflammation and decreased endothelial function occur in an animal model of metabolic syndrome, SHR/NDmcr-cp (SHR/cp) rats. The present study investigated the effects of coenzyme Q10 (CoQ10), one of the important antioxidants, on the abnormal oxidative condition and characteristic components of metabolic syndrome in SHR/cp rats by maintaining them on a diet supplemented with 0.07% - 0.7% CoQ10 for 26 weeks. We determined serum levels of oxidatively modified low-density lipoprotein (Ox-LDL) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) as oxidative stress markers, 3-nitrotyrosine as a nitrative stress marker, 3-chlorotyrosine as a marker of myeloperoxidase (MPO)-catalyzed oxidation and high-sensitivity C-reactive protein (hsCRP) as an inflammatory marker. The administration of CoQ10 significantly attenuated the increase of oxidative and nitrative stress markers and inflammatory markers in a dose-dependent manner. CoQ10 prevented the elevated serum insulin levels, although it did not affect the elevated glucose level and dyslipidemia. CoQ10 also reduced elevated blood pressure, but did not affect body weight gain. In addition, CoQ10 improved endothelial dysfunction in the mesenteric arteries. These findings suggest that the antioxidant properties of CoQ10 can be effective for ameliorating cardiovascular risk in MetS.

Kobayashi A, Utsunomiya Y, Kono M, Ito Y, Yamamoto I, Osaka N, Hasegawa T, Hoshina S, Yamaguchi Y, Kawaguchi Y, Hosoya T. · Department of Internal Medicine, Division of Kidney and Hypertension, The Jikei University School of Medicine, Tokyo, Japan. · Am J Kidney Dis. · Pubmed #18215711 No free full text.

This publication has no abstract.

Kagota S, Tada Y, Kubota Y, Nejime N, Yamaguchi Y, Nakamura K, Kunitomo M, Shinozuka K. · Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Japan. · J Cardiovasc Pharmacol. · Pubmed #18091585 No free full text.

Abstract: SHR/NDmcr-cp (SHR-cp) rats display typical symptoms and features of the metabolic syndrome. We previously reported that endothelium-dependent relaxation decreases in the thoracic aortas of SHR-cp rats, despite increased nitric oxide (NO) production from the endothelium. In the present study, to search for the reasons for this contradiction, we investigated whether vascular abnormality could be reduced by treatment of SHR-cp rats with antihypertensive drugs; a calcium channel blocker (amlodipine), an alpha 2 and imidazoline receptor agonist (moxonidine), and an angiotensin II type 1 (AT1) receptor antagonist (telmisartan). Telmisartan but not amlodipine and moxonidine ameliorated the impairment of relaxation in response to acetylcholine and the increased protein expression of endothelium NO synthase in thoracic aortas. All three drugs significantly lowered the blood pressure. Telmisartan decreased the serum levels of lipid peroxide and 8-hydroxy-2'-deoxyguanosine, oxidative stress markers, and also the aortic levels of the protein expression of gp91, a component of NADPH oxidase, and 3-nitrotyrosine, a biomarker of peroxynitrite. These findings suggest that NADPH oxidase-derived superoxide, probably produced due to stimulation of AT1 receptors, reacts with NO to form peroxynitrite, and consequently decreases active NO, leading to attenuation of endothelium-dependent relaxation. Angiotensin receptor antagonists may be effective for preventing endothelial dysfunction in metabolic syndrome.

Bode L, Salvestrini C, Park PW, Li JP, Esko JD, Yamaguchi Y, Murch S, Freeze HH. · Burnham Institute for Medical Research, La Jolla, California 92037, USA. · J Clin Invest. · Pubmed #18064305 links to  free full text

Abstract: Patients with protein-losing enteropathy (PLE) fail to maintain intestinal epithelial barrier function and develop an excessive and potentially fatal efflux of plasma proteins. PLE occurs in ostensibly unrelated diseases, but emerging commonalities in clinical observations recently led us to identify key players in PLE pathogenesis. These include elevated IFN-gamma, TNF-alpha, venous hypertension, and the specific loss of heparan sulfate proteoglycans from the basolateral surface of intestinal epithelial cells during PLE episodes. Here we show that heparan sulfate and syndecan-1, the predominant intestinal epithelial heparan sulfate proteoglycan, are essential in maintaining intestinal epithelial barrier function. Heparan sulfate- or syndecan-1-deficient mice and mice with intestinal-specific loss of heparan sulfate had increased basal protein leakage and were far more susceptible to protein loss induced by combinations of IFN-gamma, TNF-alpha, and increased venous pressure. Similarly, knockdown of syndecan-1 in human epithelial cells resulted in increased basal and cytokine-induced protein leakage. Clinical application of heparin has been known to alleviate PLE in some patients but its unknown mechanism and severe side effects due to its anticoagulant activity limit its usefulness. We demonstrate here that non-anticoagulant 2,3-de-O-sulfated heparin could prevent intestinal protein leakage in syndecan-deficient mice, suggesting that this may be a safe and effective therapy for PLE patients.

Maibaum J, Stutz S, Göschke R, Rigollier P, Yamaguchi Y, Cumin F, Rahuel J, Baum HP, Cohen NC, Schnell CR, Fuhrer W, Gruetter MG, Schilling W, Wood JM. · Novartis Institutes for BioMedical Research, NOVARTIS Pharma AG, WKL-136.683, CH-4002 Basel, Switzerland. · J Med Chem. · Pubmed #17824680 No free full text.

Abstract: Due to its function in the rate limiting initial step of the renin-angiotensin system, renin is a particularly promising target for drugs designed to control hypertension, a growing risk to health worldwide. Despite vast efforts over more than two decades, no orally efficacious renin inhibitor had reached the market. As a result of a structure-based topological design approach, we have identified a novel class of small-molecule inhibitors with good oral blood-pressure lowering effects in primates. Further lead optimization aimed for improvement of in vivo potency and duration of action, mainly by P2' modifications at the hydroxyethylene transition-state isostere. These efforts resulted in the discovery of aliskiren (46, CGP060536B, SPP100), a highly potent, selective inhibitor of renin, demonstrating excellent efficacy in sodium-depleted marmosets after oral administration, with sustained duration of action in reducing dose-dependently mean arterial blood pressure. Aliskiren has recently received regulatory approval by the U.S. Food and Drug Administration for the treatment of hypertension.

Yamamoto I, Horita S, Takahashi T, Tanabe K, Fuchinoue S, Teraoka S, Hattori M, Yamaguchi Y. · Department of Internal Medicine, Division of Kidney and Hypertension, The Jikei University School of Medicine. · Am J Transplant. · Pubmed #17617859 No free full text.

Abstract: Transplant glomerulopathy (TG) is a prominent feature of chronic rejection that is characterized by double contours of the glomerular capillaries (GC). In this report, we demonstrate that one of the histopathological features of TG is a phenotypic change of glomerular endothelial cells which is illustrated by increased caveolae formation. To verify the endothelial changes in this disease, we examined the expression of plasmalemmal vesicle-associated protein-1 (PV-1), a glycoprotein associated with plasmalemmal vesicles (caveolae), in the glomeruli of TG patients using pathologische anatomie Leiden-endothelium (PAL-E) antibody. Twenty-six cases of chronic allograft nephropathy (CAN) with TG were examined, compared with 16 cases of CAN without TG, type I MPGN (4 cases), and transplant glomerulitis (8 cases). Overall, 24 of 26 (92.3%), 4 of 16 (25%), 0 of 4, 0 of 8 cases were PAL-E-positive for GC, respectively. Further, the extent of glomerular PAL-E expression was positively correlated with both the grade of TG (rs= 0.72, p = 0.0003) and proteinuria (g/day) (rs= 0.51, p = 0.02). A correlation was not observed between glomerular PAL-E positivity and peritubular capillary C4d deposits (Yetes chi = 0.23, p = 0.89). In summary, the present study demonstrates expression of PV-1 in the GC of TG which is correlated with the grade of TG and proteinuria.

Yamamoto H, Teramoto S, Yamaguchi Y, Hanaoka Y, Ishii M, Hibi S, Ouchi Y. · Department of Geriatric Medicine, Faculty of Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. · Sleep Med. · Pubmed #17512795 No free full text.

Abstract: BACKGROUND AND PURPOSE: Obstructive sleep apnea syndrome (OSAS) is recognized as one of the risk factors of hypertension and cardiovascular disorders. In the current study, we hypothesized that the hypoxic stress caused by obstructive sleep apnea would increase circulating adrenomedullin (ADM) levels in untreated OSAS patients compared to an age-matched control group. We further hypothesized that oxygen administration treatment may decrease OSAS-induced hypoxic stress and ADM levels. METHODS: We examined short-term and long-term oxygen administration effects on circulating ADM in 48 OSAS patients. RESULTS: The circulating levels of ADM in untreated OSAS patients were significantly greater than those in the controls. We did not observe a significant effect in 2 weeks of oxygen administration on the circulating ADM in the patients, but we observed a significant effect in long-term oxygen administration for more than 3 months on plasma ADM levels. Long-term oxygen therapy decreased both the magnitude of arterial oxygen desaturation and plasma ADM levels in patients but did not decrease blood pressure. CONCLUSIONS: These observations suggest that long-term oxygen therapy could reduce OSAS-induced nocturnal hypoxemia and plasma ADM levels in patients with OSAS.

Yamamoto I, Yamaguchi Y, Yamamoto H, Hosoya T, Horita S, Tanabe K, Fuchinoue S, Teraoka S, Toma H. · Division of Kidney and Hypertension, The Jikei University School of Medicine, Tokyo, Japan. · Transplant Proc. · Pubmed #17175254 No free full text.

Abstract: Lymphatic vessels are an essential part of the immunological response. Nevertheless, little is known about the pathology of renal transplant rejection. In part the reason may be not distinguishing peritubular capillaries from lymphatic vessels by periodic acid-Schiff (PAS) staining. This study examined the morphology of lymphatic vessels in early renal allografts using double staining with PAS and podoplanin. The 41 cases were divided into four categories: (I) acute antibody-mediated rejection, (II) acute cellular rejection, (III) peritubular capillaritis only, and (IV) controls. I through III had the evidence of peritubular capillaritis exceeding grade 1 on a biopsy obtained an average of 17.3 +/- 5.5 days after kidney transplantation. In addition, each lymphatic vessel density (LVD) and nodular lesion of lymphocytes (NL) were quantified as the number of each podoplanin-positive vascular profiles and NL per unit area of cortex measured Lumina Vision (Mitani). The average of the LVD was 73.0, 35.1, 37.1, and 8.1 per 10 mm2 for groups I to IV and the average of NL was 2.8, 5.5, 1.3, 0.9, respectively. There was a significant correlation between LVD and NL. NL showed a strong relation to the accumulation of lymphocytes in lymphatic vessels (AL); 22% of the AL scores were greater than the peritubular capillaritis grade. We found lymphatic vessels to be strongly associated with any kind of inflammatory process that occurred unexpectedly soon after kidney transplantation. In addition, to avoid misdiagnosis of peritubular capillaritis, NL in early renal allograft must especially be excluded.

Yamaguchi Y, Yamada K, Yoshikawa N, Nakamura K, Haginaka J, Kunitomo M. · Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, 11-68, Koshien Kyuban-cho, Nishinomiya 663-8179, Japan. · Life Sci. · Pubmed #16959274 No free full text.

Abstract: Corosolic acid (CRA), a constituent of banaba leaves, has been reported to have anti-inflammatory and hypoglycemic activities. The aim of this study was to determine the effects of CRA on metabolic risk factors including obesity, hypertension, hyperinsulinemia, hyperglycemia, and hyperlipidemia together with oxidative stress and inflammation, all of which are characteristic of the SHR/NDmcr-cp (cp/cp) (SHR-cp) rat, an animal model of metabolic syndrome. Six-week-old male SHR-cp rats were fed a high fat diet containing 0.072% CRA for 14 weeks. Treatment with CRA lowered blood pressure, which was elevated in control animals, by 10% after 8 weeks, and serum free fatty acids by 21% after 2 weeks. CRA treatment resulted in decreases in the levels of the oxidative stress markers thiobarbituric acid-reactive substances and 8-hydroxydeoxyguanosine by 27% and 59%, respectively, after 2 weeks. CRA treatment also reduced the levels of myeloperoxidase markers, 3-nitrotyrosine and 3-chlorotyrosine by 38% and 39%, respectively, after 10 weeks, and tended to decrease the levels of high sensitivity C-reactive protein, a marker of inflammation, after 6 weeks. However, CRA had no effect on weight gain or hyperglycemia. These results demonstrate that CRA can ameliorate hypertension, abnormal lipid metabolism, and oxidative stress as well as the inflammatory state in SHR-cp rats. This implies that CRA can be beneficial for preventing atherosclerosis-related diseases that are an increasing health care problem worldwide.

Yamamoto I, Yamamoto H, Mitome J, Tanno Y, Utsunomiya Y, Miyazaki Y, Yamaguchi Y, Hosoya T. · Division of Kidney and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan. · Clin Transplant. · Pubmed #16848868 No free full text.

Abstract: Although recurrent diabetic nephropathy is common in patients with type I diabetes after kidney transplantation, the development of focal segmental glomerulosclerosis (FGS) is rare, and its development generally takes several years. We report here a case of type I diabetes mellitus with secondary FGS accompanied by proteinuria 10 months following kidney transplantation. Episode biopsy showed secondary FGS, evidenced by glomerular capillary collapse and large epithelial cells with ballooning degeneration. Exudative dense deposition of IgM in a diffuse global mesangial pattern and enlarged glomerular diameters were observed, suggestive of glomerular hyperfiltration which can lead to secondary FGS. An imbalance in body size between donor and recipient and/or uncontrolled diabetes are potential causes of glomerular hyperfiltration. We administered angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker to reduce hyperfiltration-induced renal damage; the combination therapy reduced proteinuria from 2346 to 258 mg/d. Secondary FGS should be a consideration after kidney transplantation in patients with type I diabetes mellitus.

Kagota S, Yamaguchi Y, Tanaka N, Kubota Y, Kobayashi K, Nejime N, Nakamura K, Kunitomo M, Shinozuka K. · Department of Pharmacology, School of Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Japan. · Life Sci. · Pubmed #16188278 No free full text.

Abstract: Metabolic syndrome is a cluster of metabolic abnormalities, including hypertension, hyperlipidemia, hyperinsulinemia, glucose intolerance and obesity. In such lifestyle-related diseases, impairment of nitric oxide (NO) production or bioactivity has been reported to lead to the development of atherogenic vascular diseases. Therefore, in the present study we investigated changes in the NO/cyclic guanosine monophosphate (cGMP) system in aortas of SHR/NDmcr-cp (cp/cp) rats (SHR-cp), a model of the metabolic syndrome. In aortas of SHR-cp, endothelium-dependent relaxations induced by acetylcholine and endothelium-independent relaxations induced by sodium nitroprusside were significantly impaired in comparison with Wistar-Kyoto rats. Furthermore, protein levels of soluble guanylyl cyclase and cGMP levels induced by sodium nitroprusside were significantly decreased. In contrast, protein levels of endothelium NO synthase and cGMP levels induced by acetylcholine were significantly increased, and plasma NO2 plus NO3 levels were also increased. The levels of lipid peroxide in plasma and the contents of 3-nitrotyrosine, a biomarker of peroxynitrite, in aortas were markedly increased. These findings indicate that in the aortas of SHR-cp, NO production from the endothelium is augmented, although the NO-induced relaxation response is impaired. Enhanced NO production may be a compensatory response to a variety of factors, including increases in oxidative stress.

Nishitani Y, Iwano M, Yamaguchi Y, Harada K, Nakatani K, Akai Y, Nishino T, Shiiki H, Kanauchi M, Saito Y, Neilson EG. · First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. · Kidney Int. · Pubmed #16105038 No free full text.

Abstract: BACKGROUND: There is little direct evidence that fibroblasts are involved in the progression of the renal interstitial fibrosis in human glomerulonephritis. With the availability of a new specific marker for fibroblasts, we determined the presence of fibroblasts in kidneys with IgA nephropathy (IgAN) and correlated their numbers with various clinical parameters. In particular, we also prospectively asked if the number of fibroblasts in the renal interstitium correlates with prognosis. METHODS: Cells positive for fibroblast-specific protein 1 (FSP1) were localized in renal biopsy specimens using immunohistochemistry with anti-FSP1 antibody. Clinical features were analyzed by one-way analysis of variance (ANOVA) with the Bonferroni correction. To assess the prognostic impact of the number of FSP1+ fibroblasts on renal survival in 142 patients with normal serum creatinine, the relationship between covariates to renal survival were evaluated univariately using the log-rank test and multivariately using Cox proportional hazards. RESULTS: Fibroblasts identified by their expression of FSP1 accumulate in areas showing severe interstitial fibrosis. Some tubular epithelial cells undergoing epithelial-mesenchymal transition (EMT) in fibrotic areas also express FSP1. Numbers of FSP1+ fibroblasts directly correlate with serum creatinine (r = 0.74, P < 0.0001) and inversely correlate with estimated creatinine clearance (r = -0.54, P < 0.0001), and by multivariate analysis, the clinical factors influencing renal survival are urinary protein excretion [> or = 1.0 g/day, relative risk (RR) = 4.20, P= 0.032], hypertension (RR 5.85, P = 0.0027), and > or = 20 FSP1+ fibroblasts per high power field (HPF) (RR 7.39, P = 0.0015). Staining for FSP1+ fibroblasts is largely nonoverlapping with alpha-smooth muscle actin+ (alpha-SMA) cells in the interstitium. CONCLUSION: The target protein FSP1 identifies human fibroblasts and tubular epithelium undergoing EMT, and distinguishes them from the diaspora of alpha-SMA+ vascular smooth muscle cells. FSP1+ fibroblasts are critically related to the progression of IgAN; consequently, staining FSP1 in renal biopsy specimens provides a valuable histologic index of progression.

Hara S, Yamaguchi Y, Hara S, Tanimoto A, Seki K, Matsushita H, Tomikawa S, Kuzuhara K. · Department of Pathology, Toranomon Hospital, Tokyo, Japan. · Clin Transplant. · Pubmed #15955167 No free full text.

Abstract: We conducted the present study to elucidate the fate of post-transplant mesangial IgA deposit under the long-term observation. Out of a total of 45 cases with post-transplant mesangial IgA deposition, nine cases with more than 4 yr of follow-up term were enrolled in this study, and clinicopathologic characteristics were described. The study included three men and six women with a mean age of 34.2 yr. The average observation time from the detection of mesangial IgA deposition was 6.1 yr. Three cases were categorized as recurrent IgA nephropathy, while six cases were classified into latent mesangial IgA deposition. One case with hypertension developed end-stage renal disease. The significant improvement in microscopic hematuria was observed in one recurrent IgA nephropathy case. Microscopic findings included mild mesangial stalk thickening in all but one case. IgA deposition demonstrated a significant decrease in three latent mesangial IgA deposition cases. No apparent reduction in dense deposit quantity was observed on electron microscopy. There was no association between clinicopathologic findings and the regimen of anti-immunosuppressive agents. This study showed the improvement of the disease activity did occur in both recurrent IgA nephropathy and latent mesangial IgA deposition. Further investigation of latent mesangial IgA deposition may present the important clue to the pathogenesis of IgA nephropathy.

Hashimoto M, Kubota Y, Tanaka N, Yamaguchi Y, Fujii Y, Kagota S, Kawakita E, Shido O, Kunitomo M, Shinozuka K. · Department of Environmental Physiology, Shimane University Faculty of Medicine, Izumo, Japan. · Clin Exp Pharmacol Physiol. · Pubmed #15649293 No free full text.

Abstract: 1. It has been suggested that hypertension, hyperlipidaemia and diabetes participate in the onset and development of dementia. 2. To understand cognitive dysfunction in metabolic syndrome, the relationship between the plasma and the hippocampus regarding fatty acid composition and lipid peroxidation was estimated in genetically hypertensive and obese SHR/NDmcr-cp rats (SHR-cp) aged 7-9 and 18-20 weeks. 3. Levels of total fatty acids and lipid peroxide in the plasma were much higher (by 200-500%) in SHR-cp compared with age-matched control rats (Wistar-Kyoto rats). However, in the hippocampus these levels were not significantly different between the two groups of rats. 4. Levels of hippocampal lipid peroxide in both groups increased significantly with ageing. 5. These results indicate that, in SHR-cp, lipid peroxidation in the hippocampus would not be affected even if plasma levels of fatty acids and lipid peroxide increased markedly, when ageing is not a predicative factor.

Kagota S, Tanaka N, Kubota Y, Yamaguchi Y, Nakamura K, Kunitomo M, Shinozuka K. · Department of Pharmacology, School of Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Japan. · Clin Exp Pharmacol Physiol. · Pubmed #15649291 No free full text.

Abstract: 1. Abnormal vasorelaxation responses are seen in the context of various disease states, including obesity, hypertension, hyperlipidemia and diabetes. Metabolic syndrome, which is characterized by the concomitant presence of all of these disease states, develops spontaneously in the SHR/NDmcr-cp (cp/cp) rat (SHR-cp). The goal of the present study was to determine whether abnormal vasorelaxation responses were present with metabolic syndrome. 2. Acetylcholine-induced endothelial-dependent relaxation was significantly enhanced in aortas isolated from SHR-cp at the age of 18 weeks when compared to that from control rats [lean littermates SHR/NDmcr-cp (+/+) (SHR)]. In contrast, endothelium-independent relaxation in response to sodium nitroprusside was equally attenuated in the two rat groups compared with normotensive Wistar-Kyoto rats. 3. These results suggest that endothelial nitric oxide (NO) production increased in the aorta of SHR-cp as compared to SHR. This may compensate for the concomitant impairment in the NO-mediated relaxation response in smooth muscle cells, that probably results from hypertension. Enhanced NO production may result from a variety of factors, including increases in oxidative stress in the context of the metabolic syndrome.

Wood JM, Maibaum J, Rahuel J, Grütter MG, Cohen NC, Rasetti V, Rüger H, Göschke R, Stutz S, Fuhrer W, Schilling W, Rigollier P, Yamaguchi Y, Cumin F, Baum HP, Schnell CR, Herold P, Mah R, Jensen C, O'Brien E, Stanton A, Bedigian MP. · Novartis Institute for Biomedical Research, Klybeckstrasse 220, CH-4002 Basel, Switzerland. · Biochem Biophys Res Commun. · Pubmed #12927775 No free full text.

Abstract: Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure, the leading causes of death in the Western world. Inhibitors of the renin-angiotensin system (RAS) have proven to be successful treatments for hypertension. As renin specifically catalyses the rate-limiting step of the RAS, it represents the optimal target for RAS inhibition. Several peptide-like renin inhibitors have been synthesized previously, but poor pharmacokinetic properties meant that these compounds were not clinically useful. We employed a combination of molecular modelling and crystallographic structure analysis to design renin inhibitors lacking the extended peptide-like backbone of earlier inhibitors, for improved pharmacokinetic properties. This led to the discovery of aliskiren, a highly potent and selective inhibitor of human renin in vitro, and in vivo; once-daily oral doses of aliskiren inhibit renin and lower blood pressure in sodium-depleted marmosets and hypertensive human patients. Aliskiren represents the first in a novel class of renin inhibitors with the potential for treatment of hypertension and related cardiovascular diseases.