Biomedical subjects

Shigeru Shibata

Publications and source records attributed to Shigeru Shibata.

13 recordsLinked to original sources

PubMed2007

Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1.

Accumulating evidence suggests that mineralocorticoid receptor blockade effectively reduces proteinuria in hypertensive patients. However, the mechanism of the antiproteinuric effect remains elusive. In this study, we investigated the effects of aldosterone on podocyte, a key player of the glomerular filtration barrier. Uninephrectomized rats were continuously infused with aldosterone and fed a high-salt diet. Aldosterone induced proteinuria progressively, associated with blood pressure elevation. Notably, gene expressions of podocyte-associated molecules nephrin and podocin were markedly decreased in aldosterone-infused rats at 2 weeks, with a gradual decrease thereafter. Immunohistochemical studies and electron microscopy confirmed the podocyte damage. Podocyte injury was accompanied by renal reduced nicotinamide-adenine dinucleotide phosphate oxidase activation, increased oxidative stress, and enhanced expression of aldosterone effector kinase Sgk1. Treatment with eplerenone, a selective aldosterone receptor blocker, almost completely prevented podocyte damage and proteinuria, with normalization of elevated reduced nicotinamide-adenine dinucleotide phosphate oxidase activity. In addition, proteinuria, podocyte damage, and Sgk1 upregulation were significantly alleviated by tempol, a membrane-permeable superoxide dismutase, suggesting the pathogenic role of oxidative stress. Although hydralazine treatment almost normalized blood pressure, it failed to improve proteinuria and podocyte damage. In cultured podocytes with consistent expression of mineralocorticoid receptor, aldosterone stimulated membrane translocation of reduced nicotinamide-adenine dinucleotide phosphate oxidase cytosolic components and oxidative stress generation in podocytes. Furthermore, aldosterone enhanced the expression of Sgk1, which was inhibited by mineralocorticoid receptor antagonist and tempol. In conclusion, podocytes are injured at the early stage in aldosterone-infused rats, resulting in the occurrence of proteinuria. Aldosterone can directly modulate podocyte function, possibly through the induction of oxidative stress and Sgk1.

Aldosterone↗

PubMed2006

Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors.

Metabolic syndrome is an important risk factor for proteinuria and chronic kidney disease independent of diabetes and hypertension; however, the underlying mechanisms have not been elucidated. Aldosterone is implicated in target organ injury of obesity-related disorders. This study investigated the role of aldosterone in the early nephropathy of 17-wk-old SHR/NDmcr-cp, a rat model of metabolic syndrome. Proteinuria was prominent in SHR/NDmcr-cp compared with nonobese SHR, which was accompanied by podocyte injury as evidenced by foot process effacement, induction of desmin and attenuation of nephrin. Serum aldosterone level, renal and glomerular expressions of aldosterone effector kinase Sgk1, and oxidative stress markers all were elevated in SHR/NDmcr-cp. Mineralocorticoid receptors were expressed in glomerular podocytes. Eplerenone, a selective aldosterone blocker, effectively improved podocyte damage, proteinuria, Sgk1, and oxidant stress. An antioxidant tempol also alleviated podocyte impairment and proteinuria, along with inhibition of Sgk1. As for the mechanisms of aldosterone excess, visceral adipocytes that were isolated from SHR/NDmcr-cp secreted substances that stimulate aldosterone production in adrenocortical cells. The aldosterone-releasing activity of adipocytes was not inhibited by candesartan. Adipocytes from nonobese SHR did not show such activity. In conclusion, SHR/NDmcr-cp exhibit enhanced aldosterone signaling, podocyte injury, and proteinuria, which are ameliorated by eplerenone or tempol. The data also suggest that adipocyte-derived factors other than angiotensin II might contribute to the aldosterone excess of this model.

Adipocytes↗

PubMed2006

Podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and is reversed by aldosterone blocker.

Recent clinical studies implicate proteinuria as a key prognostic factor for renal and cardiovascular complications in hypertensives. The pathogenesis of proteinuria in hypertension is, however, poorly elucidated. Podocytes constitute the final filtration barrier in the glomerulus, and their dysfunction may play a pivotal role in proteinuria. In the present study, we examined the involvement of podocyte injury in Dahl salt-hypertensive rats, an animal model prone to hypertensive glomerulosclerosis, and explored the effects of inhibition of aldosterone. Four-week-old Dahl salt-resistant and salt-sensitive rats were fed a 0.3% or 8.0% NaCl diet. Some salt-loaded Dahl salt-sensitive rats were treated with a selective aldosterone blocker eplerenone (1.25 mg/g diet) or hydralazine (0.5 mmol/L). After 6 weeks, salt-loaded Dahl salt-sensitive rats developed severe hypertension, proteinuria, and glomerulosclerosis. Immunostaining for nephrin, a constituent of slit diaphragm, was attenuated, whereas expressions of damaged podocyte markers desmin and B7-1 were upregulated in the glomeruli of salt-loaded Dahl salt-sensitive rats. Electron microscopic analysis revealed podocyte foot process effacement. Podocytes were already impaired at as early as 2 weeks of salt loading in Dahl salt-sensitive rats, when proteinuria was modestly increased. Both eplerenone and hydralazine partially reduced systemic blood pressure as measured by indirect and direct methods in salt-loaded Dahl salt-sensitive rats, but only eplerenone dramatically improved podocyte damage and retarded the progression of proteinuria and glomerulosclerosis. Our findings suggest that podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and that inhibition of aldosterone by eplerenone is protective against podocyte damage, proteinuria, and glomerulosclerosis in this hypertensive model.

Animals↗

PubMed2006

Fluvastatin ameliorates podocyte injury in proteinuric rats via modulation of excessive Rho signaling.

Statins have been reported to confer renoprotection in several experimental models of renal disease through pleiotropic actions. The roles of statins in glomerular podocytes have not been explored. The objective of this study was to evaluate the effects of fluvastatin on podocyte and tubulointerstitial injury in puromycin aminonucleoside (PAN)-induced nephrosis. PAN induced massive proteinuria and serum creatinine elevation on day 7, which were significantly suppressed by fluvastatin. Immunofluorescence studies of podocyte-associated proteins nephrin and podocin revealed diminished and discontinuous staining patterns in rats with PAN nephrosis, indicating severe podocyte injury. Fluvastatin treatment dramatically mitigated the abnormal staining profiles. Reduction of nephrin expression by PAN and its reversal by fluvastatin were confirmed by quantitative analyses. By electron microscopy, effacement of foot processes was ameliorated in fluvastatin-treated rats. Fluvastatin also mitigated tubulointerstitial damage in PAN nephrosis, with the repression of PAN-induced NF-kappaB and activator protein-1 activation in the kidneys. In addition, expression of activated membrane-bound small GTPase RhoA was markedly increased in the glomeruli of PAN nephrosis, which was inhibited by fluvastatin treatment. In cultured podocytes, fluvastatin suppressed PAN-evoked activation of RhoA and actin cytoskeletal reorganization. Furthermore, fasudil, a specific Rho-kinase inhibitor, successfully ameliorated PAN-induced podocyte damage and proteinuria. In summary, fluvastatin alleviated podocyte and tubulointerstitial injury in PAN nephrosis. The beneficial effects of fluvastatin on podocytes can be attributable to direct modulation of excessive RhoA activity. Our data suggest a therapeutic role for statins in clinical conditions that are relevant to podocyte injury.

Acute-Phase Proteins↗

PubMed2005

Expression and regulation of adrenomedullin in renal glomerular podocytes.

Adrenomedullin (AM) is postulated to exert organ-protective effects. It is expressed in the renal glomeruli, but its roles in the glomerular podocytes have been poorly elucidated. In the present study, we investigated the expression and regulation of AM in recently established conditionally immortalized mouse podocyte cell line in vitro and podocyte injury model in vivo. The cultured differentiated podocytes expressed AM mRNA and secreted measurable amount of AM. AM secretion from the podocytes was increased by H(2)O(2), hypoxia, puromycin aminonucleoside (PAN), albumin overload, and TNF-alpha. Real-time RT-PCR analysis revealed that AM mRNA expression in the podocytes was enhanced by PAN and TNF-alpha, both of which were suppressed by mitochondrial antioxidants. Furthermore, AM expression was upregulated in the glomerular podocytes of PAN nephrosis rats. These results indicated that AM expression in the podocytes was upregulated by stimuli or condition relevant to podocyte injury, suggesting its potential role in podocyte pathophysiology.

Adrenomedullin↗

PubMed2005

[A case of a nonresected gastric cancer with peritoneal dissemination maintained on TS-1 and docetaxel combination chemotherapy with good QOL].

In general, treatment for gastric cancer with peritoneal dissemination or recurrent gastric cancer is outside the scope of surgery. The efficacy of new anti-cancer drugs such as TS-1 system was revealed in a controlled study by comparing treatment with non-treatment groups. We performed chemotherapy of TS-1 and docetaxel (TXT) in the outpatient clinic on a 72-year-old nonresected gastric cancer patient accompanied by peritoneal dissemination. Although no killer cell effect was recognized, the patient clinically achieved good QOL by this method for one year and seven months. In conclusion, we reported a treatment method for nonresected gastric cancer, which was treated only on an outpatient basis. The course of this case closely resembled the tumor dormancy therapy performed by Takahashi et al.

Adenocarcinoma↗

PubMed2005

[A Case of advanced gastric cancer successfully treated with TS-1/low-dose CDDP as neoadjuvant chemotherapy].

TS-1 was introduced into the treatment of advanced or recurrent gastric cancer cases. Along with independent administration of TS-1, a high antitumor effect has been reported in combination with various anticancer agents. We report a patient with gastric cancer successfully treated with TS-1 and low-dose CDDP as neoadjuvant chemotherapy. The patient was a 46-year-old man who was diagnosed as type 3 gastric cancer with suspected invasion of the pancreas. Histopathological findings demonstrated the degeneration of cancer cells and fibrosis in the primary tumor. The changes against neoadjuvant chemotherapy were judged to be Grade 3. The treatment was completed without adverse events. TS-1 and low-dose CDDP therapy can be one of the effective methods as neoadjuvant chemotherapy without remarkable toxicity.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Two cases of renovascular hypertension and ischemic renal dysfunction: reliable choice of examinations and treatments.

We experienced two aged patients with atherosclerotic renovascular stenosis associated with hypertension and ischemic nephropathy. Both patients exhibited sudden rise in blood pressure (BP) and progressive aggravation of renal dysfunction. In these patients, the use of contrast medium to screen for renal artery stenosis (RAS) ran the risk of further deterioration of renal function. We therefore used magnetic resonance angiography (MRA), which is less conducive to renal damage, to screen for RAS. One-sided RAS was treated by percutaneous transluminal angioplasty of the renal artery (PTRA) and stenting. As a result, BP decreased in both patients. Serum creatinine (Cr) decreased slightly in one patient, whereas, in the other, serum Cr increased transiently and then decreased and stabilized to pre-treatment levels. Thus, although it is unclear whether the combination of PTRA and stenting is among the best treatments for patients with RAS and moderate-to-severe renal dysfunction, PTRA and stenting are clearly of benefit in selected patients. In addition, recent progress in characterizing the pathophysiology of ischemic nephropathy associated with renovascular hypertension has created interest in the therapeutic potential of angiotensin II receptor antagonists, sympatholytic agents, and antioxidants. Therefore, we discuss the therapeutic utility of PTRA and stenting and the above-mentioned medications in patients with RAS and renal dysfunction.

Angioplasty, Balloon↗

PubMed2004

Severe interstitial cystitis associated with Sjögren's syndrome.

A 53-year-old woman presented with oliguria, urinary frequency, abdominal pain and severe edema of the lower extremities. Her serum creatinine was 8.1 mg/dl. Computed tomographic and ultrasonographic studies showed a severely dilated urinary bladder, and bilateral hydroureteronephrosis. Examination of a urinary bladder biopsy specimen showed subepithelial edema and infiltration by lymphocytes and plasmacytes. However, the patient complainted of dry mouth and dry eyes. Ophthalmologically, the Schirmer test was positive. A biopsy of the minor salivary glands in the lip showed chronic sialoadenitis. A diagnosis of Sjögren's syndrome complicated by interstitial cystitis was made. Since she had been anuric, secondary to urinary obstruction, intermittent self-catheterization was started. Combination of corticosteroid and cyclosporin therapy was initiated. Spontaneous urination began, and gradually the patient's symptoms remitted. After 8 months of therapy, bladder capacity increased from 140 ml to 350 ml, and she voided approximately 1,200 ml by herself and 600 ml by catheterization daily. This case suggests that when severe interstitial cystitis is associated with Sjögren's syndrome, a therapeutic trial of corticosteroids and cyclosporin may be beneficial.

Cyclosporine↗

PubMed2004

The lower pole of the earlobe is an alternative site for painless blood sampling in the self-assessment of blood glucose concentrations.

OBJECTIVES: Measurement of blood glucose is essential for better control of diabetes mellitus. The pain associated with repeated blood sampling is a significant problem, and a less painful technique would be advantageous. This study was conducted to establish a less painful method of blood sampling for monitoring of blood glucose concentrations. METHODS: Fourteen healthy doctors and nurses at the age of 22 to 32 years were enrolled into this study. The earlobe was divided into 20 areas. Each area was punctured with a fine needle and the pain was assessed by the visual analog scale (VAS). Then, localized cooling or warming was applied before puncture and the pain was assessed by the VAS. RESULTS: The VAS tended to be lower toward the lower part of the earlobe. The VAS in the uppermost area was 53.1 +/- 19.1 mm and 28.9 +/- 16.8 mm in the lowest part of the earlobe. The VAS was higher in the uppermost area than in the lowest area in six of the seven volunteers (p=0.028). We did not find significant differences in the VAS and blood glucose levels between the control sampling and the warming, or cooling sampling. The localized warming shortens the time to obtain blood by 4.4 seconds (p=0.0426). CONCLUSION: The area of the ear, but not localized cooling or warming, significantly affects the pain in sampling blood from the earlobe. Blood sampling for glucose tests are recommended to be obtained at the lower pole of the earlobe.

Adult↗

PubMed2003

Fever and anuria.

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Abdominal Abscess↗

PubMed2003

HNK-1-Reactive oligosaccharide, sulfate-O-3GlcAbeta1-4Xylbeta1-MU, synthesized by cultured human colorectal cancer cells.

Human colorectal cancer cells were incubated with medium containing 4-methylumbelliferyl-beta-D-xyloside (Xyl-MU). The cells synthesized Xyl-MU-derivatives which were detected in the culture medium by gel-filtration high-performance liquid chromatography. These included a Xyl-MU-induced glycosaminoglycan and its biosynthetic intermediates, Galbeta1-4Xylbeta1-MU and Galbeta1-3Galbeta1-4Xylbeta1-MU, and other Xyl-MU-induced oligosaccharides, not related to Xyl-MU-induced glycosaminoglycan, were also synthesized. One of these oligosaccharides, sulfate-O-3GlcAbeta1-4Xylbeta1-MU, reacted with HNK-1, a mouse monoclonal antibody raised against human natural killer cells. Human neural cells and skin fibroblasts have also been reported to synthesize HNK-1-reactive sugar chains. Since HNK-1-reactive sugar chains are known to be involved in cell adhesion in the nervous system, the present results suggest that epithelium-derived colorectal cancer cells might also be able to utilize them in cell adhesion.

Animals↗

PubMed2002

[Chemoradiotherapy using platinum analogs/5-FU for advanced esophageal cancer].

We evaluated the efficacy of concurrent chemoradiotherapy (CRT) using cisplatin/nedaplatin and 5-FU for advanced esophageal cancer. Thirteen patients with locally advanced esophageal cancer (T4 cases) and 3 with recurrence of esophageal cancer were treated with radiotherapy (40-70 Gy) and 5-FU combined with cisplatin/nedaplatin concurrently. T4 patients who obtained down-staging by CRT also underwent esophagectomy. A complete response was obtained in one case, partial response in 8 cases, and no change in 7 cases. The overall response rate was 56.3%. A pathological complete response was obtained in one case in which curative resection was performed after CRT. Bone marrow suppression was observed in 68.8% and grade 3 and 4 bone marrow suppression was observed in 43.8%. Concurrent CRT using cisplatin/nedaplatin and 5-FU for advanced esophageal cancer has a high response rate and patients obtaining down-staging by CRT as a neoadjuvant therapy have a chance for long survival after curative resection in locally advanced cases.

Adult↗