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Chikako Moriya,
Yui Shida,
Yuki Yamane,
Yuki Miyamoto,
Midori Kimura,
Naomi Huse,
Kaori Ebisawa,
Yuki Kameda,
Ayaka Nishi,
Dongdong Du,
Mariko Yoshinaga,
Itsuki Murota,
Nobuyuki Sato, Yoshio Uehara
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ABSTRACT: Objective: We investigated the mechanism of antihypertensive effects of sodium alginate oligosaccharides, which are enzymatic products of high-molecular-weight natural alginate from seaweeds, in Dahl salt-sensitive (Dahl S) rats. Materials and Methods: Dahl S rats fed a high-salt (4% NaCl) diet were subcutaneously administered sodium alginate oligosaccharides (60 mg/day using a continuous osmotic mini-pump) for 14 days. Systolic blood pressure (SBP) was measured using the tail-cuff method, and we determined the influence of the alginate treatment on the metabolism of sodium by measuring sodium excretions in the feces and urine. Results: SBP increased in an age-dependent manner in the untreated Dahl S rats. Sodium alginate oligosaccharide treatment via the subcutaneous route almost completely abolished salt-induced hypertension in Dahl S rats fed a high-salt diet. The level of fecal or urinary sodium excretion did not significantly change during the treatment period with the alginate oligosaccharides. The reduction in SBP rapidly recovered after cessation of the treatment. Moreover, the level of urinary protein excretion was lower in the treated Dahl S rats than in the untreated rats during the experimental period. Conclusions: Our results suggest that sodium alginate oligosaccharides attenuate salt-induced hypertension in Dahl S rats not through reducing salt absorption, but probably through a direct action on vascular vessels.
Clinical and Experimental Hypertension 03/2013; · 1.07 Impact Factor
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Mai Ueno,
Yuki Tamura,
Natsuko Toda,
Mariko Yoshinaga,
Shouko Terakado,
Kie Otsuka,
Atsushi Numabe,
Yukari Kawabata,
Itsuki Murota,
Nobuyuki Sato, Yoshio Uehara
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ABSTRACT: We investigated the effects of sodium alginate oligosaccharides (alginate) on the development of spontaneous hypertension in rats. Spontaneous hypertensive rats were treated with alginate for 7 weeks. Systolic blood pressure (SBP) and cardiovascular and kidney damage were assessed. Systolic blood pressure increased in SHRs and this elevation was attenuated with alginate treatment. The heart weight tended to decline. Alginate did not change plasma cholesterol levels or urinary sodium excretions. The slightly higher urinary protein excretion in SHRs was not changed with the treatment; however, morphologic glomerular damage was significantly attenuated. Sodium alginate oligosaccharide attenuates spontaneous hypertension in SHRs, and may help prevent early-stage kidney injury.
Clinical and Experimental Hypertension 06/2012; 34(5):305-10. · 1.07 Impact Factor
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ABSTRACT: We investigated the effects of long-term miso soup drinking on salt-induced hypertension in Dahl salt-sensitive (Dahl S) rats.
Dahl S rats were divided into four groups that consumed 1) water, 2) a 0.9% NaCl solution, 3) a 1.3% sodium NaCl solution, or 4) miso soup containing 1.3% NaCl. They were followed for 8 wk. Systolic blood pressure and hypertensive organ damage were determined.
Systolic blood pressure increased in an age- and dose-dependent manner in Dahl S rats drinking salt solutions. The systolic blood pressure increase was significantly less in the Dahl S rats that drank miso soup, although the ultimate cumulative salt loading was greater than that in the Dahl S rats given the 1.3% NaCl solution. This blood pressure decrease was associated with a morphologic attenuation of glomerular sclerosis in the kidney and collagen infiltration in the heart. Urinary protein excretions were less in the miso group than in the rats given the 1.3% NaCl solution. The fractional excretion of sodium was increased and that of potassium was decreased in Dahl S rats given the 1.3% NaCl solution, and these effects were reversed in rats given miso soup toward the values of the control.
We found that long-term miso soup drinking attenuates the blood pressure increase in salt-induced hypertension with organ damage. This may be caused by a possible retardation of sodium absorption in the gastrointestinal tract or by the direct effects of nutrients in the miso soup from soybeans. The decrease was associated with decreases in cardiovascular and renal damage.
Nutrition 01/2012; 28(9):924-31. · 3.03 Impact Factor
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Shouko Terakado,
Mai Ueno,
Yuki Tamura,
Natsuko Toda,
Mariko Yoshinaga,
Kie Otsuka,
Atsushi Numabe,
Yukari Kawabata,
Itsuki Murota,
Nobuyuki Sato, Yoshio Uehara
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ABSTRACT: In this article, the antihypertensive effects of sodium alginate oligosaccharides, enzymatic products of high molecular natural alginate from sea weeds, in Dahl salt-sensitive (Dahl S) rats were investigated.
Dahl S rats fed a high-salt (4% NaCl) diet were treated with sodium alginate oligosaccharides (4% or 8% w/w) for 7 weeks. Systolic blood pressure (SBP) was measured by the tail-cuff method, and hypertensive cardiovascular benefits and kidney damage were assessed. Glomerular function and morphological sclerosis were determined.
SBP increased in an age-dependent manner in the untreated Dahl S rats. Sodium alginate oligosaccharide treatment attenuated the increase in SBP in a dose-dependent manner. The heart and aortic walls weighed less in the rats treated with sodium alginate oligosaccharides than in the untreated rats. The SBP reduction was associated with a decrease in urinary protein excretion and an increase in the creatinine clearance rate. Sodium alginate oligosaccharides significantly attenuated hypertensive glomerular sclerosis and arterial injury in the kidney. Fractional excretion of sodium (FENa) decreased in low-salt Dahl S rats and increased with a salt challenge. The alginate oligosaccharides decreased FENa in high-salt Dahl S rats.
The results of this study suggest that sodium alginate oligosaccharides attenuate salt-induced hypertension in Dahl S rats. This reduction is associated with decreases in cardiovascular and renal damage.
Clinical and Experimental Hypertension 10/2011; 34(2):99-106. · 1.07 Impact Factor
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Yoshio Uehara
Nippon rinsho. Japanese journal of clinical medicine 07/2010; 68 Suppl 7:25-8.
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Yoshio Uehara
Nippon rinsho. Japanese journal of clinical medicine 07/2010; 68 Suppl 7:15-9.
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ABSTRACT: Lipocalin-type prostaglandin D synthase (L-PGDS) is a multifunctional protein that produces prostaglandin D(2) and binds and transports various lipophilic substances after secretion into various body fluids as beta-trace. L-PGDS has been proposed to be a useful diagnostic marker for renal injury associated with diabetes or hypertension, because the urinary and plasma concentrations are increased in patients with these diseases. However, it remains unclear whether urinary L-PGDS is synthesized de novo in the kidney or taken up from the blood circulation. In crude extracts of monkey kidney and human urine, we found L-PGDS with its original N-terminal sequence starting from Ala23 after the signal sequence, and also its N-terminal-truncated products starting from Gln31 and Phe34. In situ hybridization and immunohistochemical staining with monoclonal antibody 5C11, which recognized the amino-terminal Ala23-Val28 loop of L-PGDS, revealed that both the mRNA and the intact form of L-PGDS were localized in the cells of Henle's loop and the glomeruli of the kidney, indicating that L-PGDS is synthesized de novo in these tissues. However, truncated forms of L-PGDS were found in the lysosomes of tubular cells, as visualized by immunostaining with 10A5, another monoclonal antibody, which recognized the three-turn alpha-helix between Arg156 and Thr173. These results suggest that L-PGDS is taken up by tubular cells and actively degraded within their lysosomes to produce the N-terminal-truncated form.
FEBS Journal 10/2009; 276(23):7146-58. · 3.79 Impact Factor
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Kensuke Asaba,
Akihiro Tojo,
Maristela Lika Onozato,
Satoshi Kinugasa,
Hiroki Miyazaki,
Kazuhisa Miyashita, Yoshio Uehara,
Yasunobu Hirata,
Kenjiro Kimura,
Atsuo Goto,
Masao Omata,
Toshiro Fujita
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ABSTRACT: We compared the effect of treatments in the long-term renal survival of IgA nephropathy.
One hundred and fourteen patients with biopsy-proven IgA nephropathy were retrospectively divided into 4 groups, reflecting shifts in treatment trends from 1985 to 2005: patients without treatment (no treatment group; n=36), patients treated only with anti-platelet drugs (anti-platelet group; n=12), those treated mainly with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) (ACEI/ARB group; n =29), and prednisolone-treated patients (PSL group; n =37).
Baseline blood pressure, serum creatinine and renal histological findings were similar among the 4 groups; however, the urinary protein level was significantly severer in the PSL group. After a mean follow-up of 7.0+/-0.5 years, end-stage renal disease occurred in 11 patients (31%) in the no treatment group, 5 patients (42%) in the anti-platelet group and 3 patients (8%) in the PSL group, but in only 1 patient (3%) in the ACEI/ARB group. Kaplan-Meier renal survival after 20 years was significantly better in the ACEI/ARB group than in the anti-platelet group or in the no treatment group (p<0.05). The patients that reached complete remission (CR) by steroid therapy showed less baseline urinary protein and milder histological lesions than those who did not reach CR. The non-CR group showed increases in serum creatinine and eGFR reduction rate.
Treatment with renin-angiotensin system inhibitors showed the greatest improvement of 20-year renal survival in IgA nephropathy patients. Steroid therapy achieved complete remission in some early-stage cases.
Internal Medicine 01/2009; 48(11):883-90. · 0.94 Impact Factor
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ABSTRACT: Urinary excretions of lipocalin-type prostaglandin D synthase/beta-trace (L-PGDS) probably reflect the increased permeability of injured glomerular capillary walls of the kidney. We tested the hypothesis in cross-sectional and prospective studies that urinary L-PGDS excretions predict renal injury in type-2 diabetes.
(1) In the cross-sectional studies, we evaluated whether urinary L-PGDS excretions were able to predict renal diseases in a pooled population including 793 healthy subjects and 200 patients with various forms of renal diseases. (2) We determined the cut-off point of urinary L-PGDS excretions to predict >or=30 mg/gCr albuminuria in 666 patients with type-2 diabetes. (3) In the prospective study, 121 type-2 diabetic patients with <30 mg/gCr albuminuria were followed for almost 2 years to examine whether urinary L-PGDS excretions predict the future status of renal injury in type-2 diabetes.
(1) In the cross-sectional studies, receiver operating characteristic analysis revealed that urinary L-PGDS excretions better predicted the patients with kidney diseases than the other markers of renal injury. (2) It was also demonstrated that >or=4.2 mg/gCr urinary L-PGDS excretions better predicted >or=30 mg/gCr albuminuria in type-2 diabetic patients than other markers. (3) The prospective study revealed that in type-2 diabetic patients with <30 mg/ gCr albuminuria, the patients with >or=4.2 mg/gCr urinary L-PGDS excretions more likely exhibited the renal injury during the follow-up periods than those with <4.2 mg/gCr urinary L-PGDS excretions.
Urinary L-PGDS excretions reflect the current increased permeability of injured glomerular capillary walls and better predict the future status of renal injury in type-2 diabetes with <30 mg/gCr albuminuria.
Nephrology Dialysis Transplantation 10/2008; 24(2):475-82. · 3.40 Impact Factor
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ABSTRACT: Although historical support exists for the concept that breastfeeding might be protective against allergic diseases, contradictory findings have been observed recently.
To investigate the cumulative prevalence of allergic diseases in Japanese university students and to identify explanatory variables including breastfeeding.
From March 18, 2003, through March 29, 2005, a total of 9,615 students newly enrolled at the University of Tokyo responded to a written questionnaire on allergic diseases.
Cumulative prevalence of allergic rhinitis, atopic dermatitis, and asthma was 47.2%, 17.4%, and 9.3%, respectively. These data were closely correlated, and prevalence of any 1 of the 3 diseases significantly increased the odds for historical prevalence of the other 2 (P < .001). Male sex (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.4-1.7) and maternal (OR, 2.2; 95% CI, 2.0-2.5) or paternal (OR, 1.6; 95% CI, 1.4-1.8) history of allergic rhinitis were significant correlates of increased odds for allergic rhinitis. Maternal (OR, 2.7; 95% CI, 1.6-4.5), paternal (OR, 3.8; 95% CI, 2.2-6.6), or sibling (OR, 1.9; 95% CI, 1.5-2.4) history of atopic dermatitis was a significant correlate of increased odds for atopic dermatitis. As for asthma, maternal (OR, 4.9; 95% CI, 3.0-7.9), paternal (OR, 4.0; 95% CI, 2.3-7.0), or sibling (OR, 3.3; 95% CI, 2.4-4.5) history of asthma was a significant correlate of increased odds. Logistic regression analysis showed no consistent evidence of the effects of breastfeeding on the cumulative prevalence.
The cumulative prevalence of these diseases among young adults revealed that the effect of breastfeeding is negligible when compared with genetic factors.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 09/2008; 101(2):153-9. · 2.83 Impact Factor
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ABSTRACT: Abstract Monocrotaline (MCT)-induced pulmonary hypertension (PH) is a useful model for the investigation of this disorder in humans. The role of thrombocytes in the genesis of PH has already been addressed; however, the exact mechanism by which they induce PH remains to be elucidated. We investigated the effects of a thromboxane A2 (TXA2) synthase inhibitor (OKY-046) and a TXA2/ prostaglandin H2 (PGH2) receptor antagonist (ONO-8809) on the development of MCT-induced PH. A single dose of MCT (60 mg/kg bodyweight; BW) was injected subcutaneously in Wistar rats 24 h after the administration of OKY-046 or ONO-8809. The TXA2 inhibitors were administered by gavage daily for 3 weeks. Urinary excretion of eicosanoids was determined by radioimmunoassay. At the end of the treatment period, the lungs, heart and kidneys were morphologically examined. The per cent medial thickness of the muscular pulmonary arteries (%MT) and the ratio of the right to the left ventricular mass including the septum (RV/LV+S) increased significantly in MCT-treated rats compared with the control rats. The %MT was attenuated by the administration of ONO-8809. Either OKY-046 or ONO-8809 attenuated the increase in RV/LV+S. In addition, both TXA2 inhibitors reduced urinary excretion of 11-dehydro-TXB2, particularly during the early phase of PH, suggesting that platelet aggregation was reduced. These findings suggest that the inhibition of TXA2 by synthase inhibition or receptor antagonism reduces or delays the development of MCT-induced PH in rats, probably by inhibiting platelet aggregation.
Respirology 02/2008; 2(4):283 - 289. · 2.42 Impact Factor
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Ritsuko Yoshikawa,
Jun Wada,
Kousuke Seiki,
Takashi Matsuoka,
Satoshi Miyamoto,
Kenji Takahashi,
Sachiko Ota,
Kazuhi Taniai,
Kazuyuki Hida,
Minoru Yamakado,
Kenichi Shikata, Yoshio Uehara,
Yoshihiro Urade,
Hirofumi Makino
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ABSTRACT: The presence of metabolic syndrome has been shown to be predictors of cardiovascular morbidity and mortality in patients with type 2 diabetes. In a cross-sectional clinical study, we investigated the association of metabolic syndrome with asymptomatic lacunar strokes and cardiovascular disease (CVD) and we compared its significance with urinary protein markers.
We studied Japanese type 2 diabetes patients (n=233, men=124, women=109). The diagnosis of metabolic syndrome was made according to WHO and International Diabetes Federation (IDF) criteria. Cardiovascular events were recorded and asymptomatic lacunar lesions were evaluated with magnetic resonance imaging (MRI). We also measured urinary levels of albumin, type IV collagen, beta2-microglobulin (beta2MG), N-acetyl-beta-d-glucosaminidase (NAG) and lipocalin-type prostaglandin D synthase (PGDS).
The prevalence of metabolic syndrome is 31.3% (IDF) and 52% (WHO) in 233 patients and microalbuminuria was present in 62 subjects (26.6%). Metabolic syndrome (WHO) significantly associated with asymptomatic lacunar lesions (p=0.035, OR=2.854, CI 1.075-7.579), while metabolic syndrome (IDF) or urinary markers failed to associate with presence of asymptomatic lacunar lesions. The presence of metabolic syndrome or microalbuminuria did not show significant association with CVD; however, the elevation of beta2MG, NAG and PGDS showed significant association with CVD. By a logistic regression analysis using urinary proteins as independent variables, the presence of higher PGDS excretion independently associated with history of CVD (p=0.025, OR=3.847, CI 1.180-12.545).
In type 2 diabetes patients, the elevation of urinary PGDS secretion closely associated with cardiovascular events and may be a supplemental or additional marker to the criteria of metabolic syndrome.
Diabetes Research and Clinical Practice 07/2007; 76(3):358-67. · 2.75 Impact Factor
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Yoshio Uehara
Nippon rinsho. Japanese journal of clinical medicine 09/2006; 64 Suppl 6:264-70.
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Momoko Ogawa,
Nobuhito Hirawa,
Takamasa Tsuchida,
Naomi Eguchi,
Yukari Kawabata,
Atsushi Numabe,
Hideyuki Negoro,
Rie Hakamada-Taguchi,
Kousuke Seiki,
Satoshi Umemura,
Yoshihiro Urade, Yoshio Uehara
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ABSTRACT: Otsuka Long-Evans Tokushima Fatty (OLETF) rats genetically develop diabetes which is associated with hypertension. In preliminary studies, urinary excretions of L-PGDS (lipocaline-type prostaglandin D synthase) increase before diabetic nephropathy obviously develops, and this may predict progression of renal injury following diabetes. In the present study, we attempted to define whether urinary excretions of L-PGDS behave as the predictor of development of diabetic nephropathy in OLETF rats.
We investigated alterations of urinary L-PGDS excretions during the establishment of diabetes and assessed the relationship between the L-PGDS excretions and renal function in OLETF rats. Furthermore, we treated OLETF rats with troglitazone and analysed the effects on L-PGDS metabolisms. Urinary L-PGDS was measured by immunoenzyme assay and the occurrence of L-PGDS and its mRNA in the kidney was assessed by immunohistochemistry and a PCR method.
Urinary excretions of L-PGDS were significantly higher in OLETF rats than non-diabetic Long-Evans Tokushima Otsuka (LETO) rats. The excretions age-dependently increased in OLETF and this increase appeared to be due to increased glomerular permeability to L-PGDS. Messenger RNA and antigenicity of L-PGDS were demonstrated in renal tissue; however, the de novo synthesis of L-PGDS mRNA seemingly contributed to urinary L-PGDS excretions much less than glomerular filtration. Multiple regression analysis revealed that urinary L-PGDS was determined by urinary protein excretions, and not by high blood pressure per se. Conversely, urinary proteinuria in the established diabetic nephropathy was predicted by urinary L-PGDS excretions in the early stage of diabetes.
Urinary excretions of L-PGDS are likely to reflect the underlying increase in glomerular permeability. This property may be useful to predict forthcoming glomerular damage following diabetes in OLETF rats.
Nephrology Dialysis Transplantation 05/2006; 21(4):924-34. · 3.40 Impact Factor
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ABSTRACT: We examined the role of prostaglandin D(2) (PGD(2)) in the expression of vascular cell adhesion molecule-1 (VCAM)-1 following interleukin-1beta (IL-1) stimulation in human umbilical vein endothelial cells (HUVEC) transfected with lipocaline-type PGD(2) synthase (L-PGDS) genes. HUVEC were isolated from human umbilical vein and incubated with 20 U/ml IL-1 and various concentrations of authentic PGD(2). The isolated HUVEC were also transfected with L-PGDS genes by electroporation. The L-PGDS-transfected HUVEC were used to investigate the role of endogenous PGD(2) in IL-1-stimulated VCAM-1 biosynthesis. We also used an anti-PGD(2) antibody to examine whether an intracrine mechanism was involved in VCAM-1 production. PGD(2) and VCAM-1 levels were determined by radio- and cell surface enzyme-immunoassay, respectively. VCAM-1 mRNA was assessed by RT-PCR. IL-1-stimulated VCAM-1 expression by HUVEC was dose-dependently inhibited by authentic PGD(2). L-PGDS gene-transfected HUVEC produced more PGD(2) than HUVEC transfected with the reporter gene alone. IL-1 induced increases in VCAM-1 expression in HUVEC transfected with reporter genes alone. However, this effect was significantly attenuated in the case of IL-1 stimulation of HUVEC transfected with L-PGDS genes, and accompanied by an apparent suppression of VCAM-1 mRNA expression. Neutralization of extracellular PGD(2) by anti-PGD(2)-specific antibody influenced neither VCAM-1 mRNA expression nor VCAM-1 biosynthesis. In conclusion, HUVEC transfected with L-PGDS genes showed increased PGD(2) synthesis. This increase was associated with attenuation of both VCAM-1 expression and VCAM-1 mRNA expression. The results suggest that endogenous PGD(2) decreases VCAM-1 expression and VCAM-1 mRNA expression, probably through an intracrine mechanism.
Life Sciences 12/2005; 78(1):22-9. · 2.53 Impact Factor
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Yoshio Uehara
Nippon rinsho. Japanese journal of clinical medicine 09/2005; 63 Suppl 8:17-20.
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Nippon rinsho. Japanese journal of clinical medicine 09/2005; 63 Suppl 8:10-3.
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Teruhiko Toyo-Oka,
Tomie Kawada,
Jumi Nakata,
Han Xie,
Masashi Urabe,
Fujiko Masui,
Takashi Ebisawa,
Asaki Tezuka,
Kuniaki Iwasawa,
Toshiaki Nakajima, Yoshio Uehara,
Hiroyuki Kumagai,
Sawa Kostin,
Jutta Schaper,
Mikio Nakazawa,
Keiya Ozawa
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ABSTRACT: Advanced heart failure (HF) is the leading cause of death in developed countries. The mechanism underlying the progression of cardiac dysfunction needs to be clarified to establish approaches to prevention or treatment. Here, using TO-2 hamsters with hereditary dilated cardiomyopathy, we show age-dependent cleavage and translocation of myocardial dystrophin (Dys) from the sarcolemma (SL) to the myoplasm, increased SL permeability in situ, and a close relationship between the loss of Dys and hemodynamic indices. In addition, we observed a surprising correlation between the amount of Dys and the survival rate. Dys disruption is not an epiphenomenon but directly precedes progression to advanced HF, because long-lasting transfer of the missing delta-SG gene to degrading cardiomyocytes in vivo with biologically nontoxic recombinant adenoassociated virus (rAAV) vector ameliorated all of the pathological features and changed the disease prognosis. Furthermore, acute HF after isoproterenol toxicity and chronic HF after coronary ligation in rats both time-dependently cause Dys disruption in the degrading myocardium. Dys cleavage was also detected in human hearts from patients with dilated cardiomyopathy of unidentified etiology, supporting a scheme consisting of SL instability, Dys cleavage, and translocation of Dys from the SL to the myoplasm, irrespective of an acute or chronic disease course and a hereditary or acquired origin. Hereditary HF may be curable with gene therapy, once the responsible gene is identified and precisely corrected.
Proceedings of the National Academy of Sciences 06/2004; 101(19):7381-5. · 9.68 Impact Factor
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ABSTRACT: Lipocalin-type prostaglandin D synthase (L-PGDS), an enzyme converting prostaglandin H(2) to prostaglandin D(2), occurs particularly in the cardiovascular system. Urinary L-PGDS excretion is increased in diabetes prior to overt proteinuria, suggesting that it is a predictor of renal injury. In this study, we tested the hypothesis that L-PGDS excretion reflects renal injury in primary glomerular diseases using Adriamycin-induced nephropathy in mice.
Twenty 6-week-old ICR female mice were intravenously given a dose of 25 mg Adriamycin/kg body weight through the tail vein. 24-hour urine was collected every day, and blood samples were obtained.
The mice developed significant albuminuria from day 3 onward (p < 0.05), which was followed by overt proteinuria from day 4 (p < 0.05). Histological examination revealed focal mesangial expansion with partial tubular atrophy. Urinary L-PGDS excretion significantly increased from day 1 onward (p < 0.05), and apparently preceded the increase in urinary albumin excretions. Either serum L-PGDS or creatinine levels were not changed by administration of Adriamycin. However, serum creatinine levels were inversely correlated to urinary L-PGDS excretions (r = -0.88, p < 0.05). Immunohistochemistry showed that L-PGDS occurred in the tubules, but not in the glomeruli in Adriamycin mice and L-PGDS mRNA paralleled urinary L-PGDS excretion.
Urinary L-PGDS excretion is increased in Adriamycin-induced nephropathy, and this precedes overt albuminuria.
Nephron Physiology 02/2004; 96(2):p42-51. · 2.55 Impact Factor
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Yoshio Uehara
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ABSTRACT: Prostaglandin D(2) (PGD(2)) and its metabolites bind to the intracellular PPARs to regulate vasoactive substances involved in vascular remodeling through regulation of mRNAs transcription as well as through receptor-mediated mechanisms. PGD(2) decreases inducible NO, PAI-1, endothelin, and VCAM expression through inhibition to NF kappa B, STAT, or AP-1 transcription factors, which are regulated by cytokines/immune system. Moreover, transfer of L-PGDS (PGD(2) synthase) into the intracellular space of EC or SMC increases intracellular PGD(2), thereby decreasing these substances. PGD(2) attenuates in vivo organ injury mediated by cytokines and the immune system. The pretreatment with PGD(2) attenuates the liver damage and hemodynamic collapse following LPS. Dahl salt-sensitive rats, with decreased PGD(2) in the outer medulla of the kidney, are prone to hypertensive kidney injury. Serum L-PGDS level is increased in renal dysfunction through a decrease in glomerular filtration. L-PGDS in urine may be derived from a failure of tubular reabsorption or from in situ synthesis. Urinary L-PGDS excretion markedly increases in the early stage of kidney injury, and urinary L-PGDS is a useful predictor of the forthcoming renal injury. Indeed, urinary L-PGDS precedes clinically overt proteinuria or other parameters indicating renal dysfunction in hypertension, primary renal diseases, and diabetes in humans. PGD(2)/L-PGDS system is a Cinderella of vascular biology.
Folia Pharmacologica Japonica 02/2004; 123(1):23-33.
