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Masanori Tokumoto

Publications and source records attributed to Masanori Tokumoto.

18 recordsLinked to original sources
PubMed2006

Expression of synaptopodin and GLEPP1 as markers of steroid responsiveness in primary focal segmental glomerulosclerosis.

The crucial involvement of podocyte failure in the development of hereditary focal segmental glomerulosclerosis (FSGS) indicates that specific podocyte proteins are closely related to podocyte function and biology. We hypothesized that podocyte failure, reflected by alteration of these proteins, leads not only to FSGS but also to resistance to steroid therapy. We investigated the association between expression of synaptopodin and glomerular epithelial protein 1 (GLEPP1) and response to corticosteroid therapy in primary FSGS. The subjects of this retrospective study were 17 adult patients with primary FSGS with nephrotic syndrome (NS) seen at Fukuoka Red Cross Hospital between 1979 and 2001. They were divided into two groups according to the response to steroid therapy at 6months: responders (n=10) and non-responders (persistence of nephrotic-range proteinuria, n=7). Expression levels of synaptopodin and GLEPP1 were examined immunohistochemically using image analysis software. Low expression levels of both proteins were associated with poor steroid responsiveness in FSGS. The average gray values for synaptopodin and GLEPP1 expression in responders vs. non-responders were 9.0+/-0.7 (mean+/-S.E.M.) vs. 6.3+/-0.9 (P=0.04) and 9.6+/-1.2 vs. 6.0+/-1.0 (P=0.04), respectively. The percentages of glomerular area staining for synaptopodin and GLEPP1 in responders vs. non-responders were 15.4+/-2.7% vs. 8.1+/-1.2% (P=0.045) and 11.9+/-1.6% vs. 6.0+/-1.3% (P=0.02), respectively. Synaptopodin expression correlated with the severity of proteinuria and with GLEPP1 expression. Reduced expression of both synaptopodin and GLEPP1 is associated with poor response to steroid therapy in primary FSGS.

Adult↗
PubMed2005

Catastrophic antiphospholipid antibody syndrome following initiation of hemodialysis.

Antiphospholipid syndrome (APS) is associated with arterial and venous thrombosis, pregnancy morbidity, and thrombocytopenia. Some APS patients develop rapid and disseminated microthrombosis and are known as having catastrophic APS or CAPS. We document here a case of CAPS in a patient who presented with various clinical symptoms and serious abnormalities of blood coagulation following initiation of hemodialysis after bilateral nephrectomy due to renal cancer. The patient developed multiple organ symptoms, including melena, visual disturbances, skin eruptions, lymph node swelling, urinary tract bleeding, backache, arteriovenous fistula occlusion, and chest pain. Based on the clinical course and serological and histological examinations, a diagnosis of CAPS was established. The patient recovered by following intensive anticoagulation and steroid therapy. Although CAPS is rare, once symptoms develop the condition deteriorates rapidly. Because of the associated high mortality, early diagnosis and prompt treatment are necessary.

Antiphospholipid Syndrome↗
PubMed2005

Increased renal resistive index in atherosclerosis and diabetic nephropathy assessed by Doppler sonography.

OBJECTIVE: The renal resistive index (RI) and pulsatility index (PI), measured using Doppler ultrasonography, reflect intrarenal vascular resistance. We evaluated the relationship between these indices and pulse wave velocity (PWV), a measure of arterial stiffness, which reflects atherosclerosis, and determined whether renal RI and PI differ depending on the underlying renal disease. METHODS: A total of 245 inpatients with or without renal impairment who underwent ultrasonographic assessment of the renal artery were enrolled in the study. Patients with renal artery stenosis or severe renal failure (serum creatinine>or=6 mg/dl) were excluded from the study. RESULTS: In univariate analysis, the RI and PI of the main renal arteries and the interlobar arteries were significantly correlated with PWV. Multivariate analyses showed that PWV was independently associated with the RI of the main renal arteries (P<0.01, R=0.256). Patients with a creatinine level less than 3 mg/dl were divided into a control group without renal diseases and three groups with different underlying renal diseases: diabetic nephropathy, chronic glomerulonephritis, and nephrosclerosis. The RI and PI of the main renal arteries and the interlobar arteries were significantly higher in patients with diabetic nephropathy than in the other three groups, even after adjusting for multiple variables, including creatinine clearance. CONCLUSION: These results suggest that the increased RI of the renal arteries is associated with the severity of systemic atherosclerosis. Furthermore, the intrarenal vascular resistance differs depending on the underlying renal disease, and appears to increase to a greater extent in diabetic nephropathy.

Adult↗
PubMed2005

Parathyroid cell growth in patients with advanced secondary hyperparathyroidism: vitamin D receptor, calcium sensing receptor, and cell cycle regulating factors.

The parathyroid gland (PTG) is a unique endocrine organ in which the quiescent glandular cells begin to proliferate in response to the demand for maintaining calcium (Ca) homeostasis in the progressive course of renal failure, leading to secondary hypereparathyroidism (SHPT). SHPT is characterized with continuous over-secretion of parathyroid hormone (PTH) and high turn-over bone disease, osteitis fibrosa, and the major factors include a deficiency of active vitamin D, hypocalcemia, and phosphate retention. With long-term end-stage renal failure, SHPT becomes resistant to conventional medical treatment such as phosphate binders and active vitamin D supplementation, and the growth of the PTG accelerates with the pattern of hyperplasia changing from diffuse to nodular type. In this process, the sigmoid curve between extracellular Ca concentration (exCa) and the plasma level of PTH shifts to the upper-rightward, indicating both an absolute increase in PTH secretion and the resistance of PT cells to exCa. Many experimental and human studies have revealed down-regulation of vitamin D receptor (VDR), calcium-sensing receptor (CaSR), and retinoid X receptor (RXR) in PT cells. The sustained proliferation of PT cells after obtaining autonomicity is another characteristic feature of SHPT. In this context, it has been demonstrated that the cell cycle is markedly progressed, where the expression of cyclin-dependent kinase inhibitor (CDKI), p21 and p27, is depressed in a VDR-dependent manner. These pathological features are most evident in nodular hyperplasia, in which monoclonal proliferation is obvious, indicating the phenotypic changes have occured in PT cells. It has been observed by Fukagawa and colleagues that pharmacologically high dose of active vitamin D administered orally can cause small-size PTG hyperplasia to regress in patients with advanced SHPT. Successful renal transplantation may also restore VDR and CaSR expressions in the diffuse type, in association with increasing TUNEL-positive cells. Thus, it is important to vigorously treat SHPT when the PT cell proliferation is in the reversible stage of diffuse hyperplasia.

Cell Cycle Proteins↗
PubMed2004

Inadequate induction of suppressor of cytokine signaling-1 causes systemic autoimmune diseases.

Suppressor of cytokine signaling (SOCS)-1 is a cytokine-inducible, negative regulatory molecule of Janus kinases (JAK) and its deficiency causes hyper-response to various cytokines. SOCS-1(-/-) mice spontaneously develop a fatal disease depending on aberrantly activated lymphocytes. Here, we show that partial restoration of SOCS-1 in lymphoid cells rescues SOCS-1(-/-) mice from the early-onset fatal disease, indicating that SOCS-1 expression in vivo is especially required in lymphocytes. However, SOCS-1 expression in these SOCS-1-restored mutant mice (E( micro )-SOCS-1(-/-) mice) was insufficient for proper down-regulation of its target signaling, and these mice spontaneously exhibit hyperactivation of lymphocytes, an increase in the levels of serum Ig and anti-DNA autoantibodies, and glomerulonephritis with glomerular IgG deposition. These phenotypes resemble those of murine systemic autoimmune diseases, models for systemic lupus erythematosus (SLE). Interestingly, similar phenotypes were also observed in adult female SOCS-1(+/-) mice, indicating that the autoimmune phenotypes of these mice can be ascribed primarily to the inadequate expression of SOCS-1. In addition, autoimmune phenotypes were not observed in SOCS-1(+/-)CD4(-/-) mice, suggesting that autoimmunity is dependent on hyper-activated CD4(+) T cells. Our findings also suggest that insufficient expression of SOCS-1 results in impaired function of CD25(+)CD4(+) regulatory T cells, which may contribute to aberrant activation of CD4(+) T cells. These findings suggest that dysfunction of SOCS-1 can be a pathogenic factor of systemic autoimmune diseases such as SLE.

Animals↗
PubMed2004

Up-regulated interleukin-4 production by peripheral T-helper cells in idiopathic membranous nephropathy.

BACKGROUND: Helper T (Th) cells are classified into Th1 and Th2 subsets based on cytokine production and the Th1/Th2 paradigm explains differences in inflammatory effector pathways in various human diseases. Membranous nephropathy (MN) is an immune complex disease associated with Th2 nephritogenic immune response. However, overproduction of interleukin (IL)-4, a principal Th2 cytokine, has not been demonstrated. We investigated Th1/Th2 cytokine production by peripheral Th cells and its association with the degree of proteinuria in MN. METHODS: We analysed production of Th1/Th2 cytokines, interferon (IFN)-gamma and IL-4 by peripheral Th cells, using an intracellular cytokine detection method with flow cytometry in patients with MN (n = 24). The data were compared with data from healthy subjects (n = 51), subjects with minimal change nephrotic syndrome (MCNS; n = 13) and subjects with focal segmental glomerulosclerosis (FSGS; n = 12). We compared the percentages of IFN-gamma+ and IL-4+ Th cells and the peripheral Th1/Th2 ratio (IFN-gamma/IL-4 ratio) among the four groups. We also examined the association of IFN-gamma and IL-4 production with clinical parameters of MN. RESULTS: The mean percentage of IL-4+ cells in MN (3.9+/-1.2%) was significantly higher than in the control (2.4+/-1.0%), MCNS (2.3+/-1.4%) and FSGS (2.3+/-1.2%) groups (P<0.001, respectively). The Th1/Th2 ratio was significantly lower in MN (5.3+/-2.0) than in the control (8.2+/-4.2, P<0.05), MCNS (10.0+/-5.3, P<0.01) and FSGS (10.2+/-5.3, P<0.01) groups. Moreover, the percentage of IL-4+ cells correlated significantly with the amount of proteinuria in MN (r = 0.57, P<0.01). CONCLUSIONS: IL-4 production by peripheral Th cells is up-regulated in patients with MN and correlated with the severity of proteinuria. Intracellular cytokine analysis could be a useful index in idiopathic MN.

Adult↗
PubMed2003

Antioxidant ameliorates cisplatin-induced renal tubular cell death through inhibition of death receptor-mediated pathways.

We have recently demonstrated the direct involvement of the death receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell (RTC) death. Reactive oxygen species are thought to be a major cause of cellular damage in such injury. The aim of this study was to examine the mechanism through which antioxidants ameliorate cisplatin-induced RTC death, with special emphasis on death receptor-mediated apoptotic pathways. Cisplatin was added to cultures of normal rat kidney (NRK52E) cells or injected in rats. NRK52E cells and rats were also treated with dimethylthiourea (DMTU), a hydroxyl radical scavenger. We then examined the mRNA levels of death ligands and receptors, caspase-8 activity, cell viability, cell death, renal function, and histological alterations. RT-PCR indicated cisplatin-induced upregulation of Fas, Fas ligand, and TNF-alpha mRNAs and complete inhibition by DMTU in vitro and in vivo. Cisplatin increased caspase-8 activity of NRK52E cells, and DMTU prevented such activation. Exposure to cisplatin reduced viability of NRK52E cells, examined by WST-1 assay, and increased apoptosis and necrosis of the cells, examined by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and fluorescence-activated cell sorter analysis. DMTU abrogated cisplatin-induced changes in cell viability and apoptosis and/or necrosis. Cisplatin-induced renal dysfunction and histological damage were also prevented by DMTU. DMTU did not hinder cisplatin incorporation into RTCs. Our results suggest that antioxidants can ameliorate cisplatin-induced acute renal failure through inactivation of the death receptor-mediated apoptotic pathways.

Animals↗
PubMed2003

Accumulation of 8-oxoguanine in the cellular DNA and the alteration of the OGG1 expression during ischemia-reperfusion injury in the rat kidney.

During ischemia-reperfusion (I/R) injury in the rat kidney, apoptosis was observed in the distal tubules of the cortico-medullary region and outer medulla (OM) while severe necrosis was seen in the proximal straight tubules of the OM. The majority of these changes disappeared within 2 weeks. We examined the contents of 8-oxo-2'-deoxyguanosine (8-oxo-dG), which is a major type of oxidative damage in DNA, in the rat kidney during I/R injury, and also investigated the expression level of the OGG1 gene encoding the 8-oxoguanine DNA glycosylase. High-performance liquid chromatography with an MS/MS analysis of the nuclear DNA revealed an immediate accumulation of 8-oxo-dG in the nuclear DNA prepared from the cortex and OM of the kidney 1h after I/R, and an immunohistochemical analysis demonstrated the immediate accumulation of 8-oxo-dG in the nuclei of renal tubular cells both in the cortex and OM. A delayed increase of cytoplasmic staining with anti-8-oxo-dG was observed only in the cortico-medulla and OM, where the cytoplasmic staining in the proximal tubular cells is higher than in the distal tubular cells. The level of cytoplasmic staining representing 8-oxo-dG in mitochondrial DNA, peaked at 6h after I/R and preceded the necrosis of proximal tubular cells in the OM. An RNase protection assay showed a high level of OGG1 mRNA in the normal kidney, and the level decreased within 3h only in the OM, and increased thereafter 1-7 days of I/R both in the cortex and OM. In situ hybridization showed higher levels of OGG1 mRNA expression in the renal tubules in the OM than in the cortex of the normal kidney, which decreased rapidly within 3h of I/R. Thus, the accumulation of 8-oxo-dG in the mitochondrial DNA rather than in nuclear DNA is likely to be involved in the pathogenic responses such as necrosis of renal tubular cells during I/R injury of the kidney, together with an altered level of OGG1 expression.

Animals↗
PubMed2003

Infusion of radiocontrast agents induces exaggerated release of urinary endothelin in patients with impaired renal function.

BACKGROUND: The aim of the study was to examine the role of endothelin in radiocontrast-induced nephropathy (RCN) in patients with chronic renal failure. METHODS: We measured plasma endothelin-1 (ET) and the urinary excretion of endothelin-like immunoreactivity before and after infusion of radio contrast medium (CM) in patients with normal renal function (group N; n = 6; mean serum creatinine concentration, 0.8 +/- 0.1 (SEM) mg/dl), and in another group, with renal dysfunction (group R; n = 6; 2.7 +/- 0.5 mg/dl). Half-normal saline (0.45% NaCl solution) was continuously infused in all patients for 25 h, at a rate of 100 ml/h; starting from 5 h before the infusion of CM. RESULTS: Plasma ET in group R (5.2 +/- 1.4 pg/ml) was significantly higher than in group N (0.9 +/- 0.3; P << 0.01). Urinary endothelin excretion corrected by creatinine concentration (uET/Cr) in group R (7.9 +/- 2.4 mg/g Cr) was significantly higher than in group N (1.5 +/- 0.4 mg/g Cr; P << 0.05). Urinary excretion levels of N-acetyl-Beta- d-glucosaminidase (NAG) and Beta2-microglobulin (Beta2M) were also significantly higher in group R (0.8 +/- 0.2 mU/g Cr and 670 +/- 400 mg/g Cr, respectively) than in group N (0.3 +/- 0.1 and 7.5 +/- 2.2, respectively). After CM infusion, uET/Cr in group R significantly increased, to 10.7 +/- 2.6 mg/g Cr on the next day and returned to baseline level on the third day. NAG and Beta2M showed a similar pattern, but a significant change in NAG was observed on the second day in group R. In group N, uET/Cr, NAG, and Beta2M did not change after CM infusion. Plasma ET remained unchanged throughout the observation period of 4 days in both groups. No patient developed pulmonary edema or a significant rise in serum creatinine (more than 0.5 mg/dl), caused by infusion of the amount of half-normal saline used. CONCLUSIONS: In the present study, uET/Cr increased after the administration of CM only in the patients with renal impairment. This difference in endothelin reaction may be a causal one, in that patients with renal insufficiency readily develop RCN. The infusion of half-normal saline starting before CM infusion causes no side effects and is safe for the prevention of CM-induced acute renal failure. The aim of the study was to examine the role of endothelin in radiocontrast-induced nephropathy (RCN) in patients with chronic renal failure.

Acetylglucosaminidase↗
PubMed2003

Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death.

BACKGROUND: Tumor necrosis factor (TNF) receptor family members, such as Fas and TNF receptor 1 (TNFR1), are thought to induce apoptosis in a variety of cells and organs. Although a number of potential scenarios have been postulated for the involvement of these receptors in the pathogenesis of acute renal failure (ARF), direct evidence for their involvement in death of renal tubular cells (RTCs) and renal dysfunction is preliminary. METHODS: This study examined the roles of these receptors in RTC death in two systems: (1). in vivo murine and rat models of cisplatin-induced ARF, and (2). murine proximal tubular cells (PTCs), which were isolated from C57BL/6 (B6) mice, Fas-mutant B6-lpr/lpr mice and TNFR1-deficient mice, and normal rat kidney (NRK52E) cells in vitro. RESULTS: Reverse transcription-polymerase chain reaction indicated cisplatin-induced up-regulation of Fas, Fas ligand and TNF-alpha mRNAs in the kidney in vivo and in RTCs in vitro, both in mice and rats. In contrast, the level of TNFR1 mRNA was substantial but did not change in response to cisplatin. TNF-alpha production in cell culture medium determined by enzyme-linked immunosorbent assay (ELISA) and Fas expression determined by fluorescence-activated cell sorter (FACS) analysis increased following incubation with cisplatin in B6 PTCs. In order to examine whether Fas and TNFR1 are directly involved in RTC death and renal dysfunction, we compared cell resistance to cisplatin using a cell viability assay and FACS analysis with fluorescein isothiocyanate-conjugated annexin V and propidium iodide staining. The ratios of cell viability loss and cell death, both from apoptosis and necrosis, were higher in B6 PTCs than in other cells, while the ratios were comparable between Fas-mutant PTCs and TNFR1-deficient PTCs. Caspase-8 activity was increased in B6 PTCs, but not in Fas-mutant PTCs and TNFR1-deficient PTCs. Furthermore, the renal dysfunction and RTC death, both apoptosis and necrosis, induced by cisplatin were more severe in B6 mice in vivo. CONCLUSION: Based on these data, we conclude that the Fas- and TNFR1-mediated apoptotic pathways are directly involved in the pathogenesis of cisplatin-induced RTC death process.

Acute Kidney Injury↗
PubMed2003

Parathyroid cell growth in patients with advanced secondary hyperparathyroidism: vitamin D receptor and cyclin-dependent kinase inhibitors, p21 and p27.

Uraemic patients with advanced secondary hyperparathyroidism (2HPT) have nodular hyperplastic glands with a decreased vitamin D receptor (VDR) density. Previous studies have shown that nodular hyperplasia expressed a significantly lower VDR density as compared with diffuse hyperplasia, and the VDR density negatively correlated with both the glandular weight and the marker of cell proliferation. However, the mechanism by which the decreased VDR density leads to parathyroid cell proliferation remains unclear. In the myelomonocytic cell line, active vitamin D(3) is known to activate the transcription of both p21 and p27, cyclin-dependent kinase inhibitors (CDKIs), regulating the transition from the G(1) to the S phase of the cell cycle, in a VDR-dependent manner. Moreover, the overexpression of p21 and p27 inhibits cell proliferation. In order to elucidate the mechanism of parathyroid cell proliferation, the expression of CDKIs, p21 and p27, and the VDR was analysed immunohistochemically, and compared among nodular and diffuse hyperplastic parathyroid glands, and histologically normal parathyroid glands. The VDR expression in nodular hyperplasias was significantly decreased compared with either diffuse hyperplasias or normal parathyroid glands. The expression of both p21 and p27 was also significantly lower in nodular hyperplasias than in diffuse hyperplasias or normal parathyroid glands. Sections of parathyroid glands with a high expression of nuclear VDR highly expressed both p21 and p27. In nodular hyperplasias, the expression of both p21 and p27 correlated either positively with the nuclear VDR expression or inversely with the glandular weight. Therefore, the reduced expression of p21 and p27, being VDR dependent, is a major pathogenic factor for nodular parathyroid gland growth in advanced 2HPT.

Animals↗
PubMed2002

Different effects of 22-oxacalcitriol and calcitriol on the course of experimental chronic renal failure.

Calcitriol, 1,25(OH)(2)D(3), has been reported to have a beneficial effect on bone histology in patients with predialysis chronic renal failure; however, such treatment involves a risk of hypercalcemia. To investigate the effects of 1,25(OH)(2)D(3) and 22-oxacalcitriol (OCT) on the progression of histologic deterioration, we administered intraperitoneal 1,25(OH)(2)D(3) or OCT, three times a week, to rats with adriamycin-induced progressive renal failure, from the 10th week after the induction of ADR-induced nephropathy. The rats were divided into the following groups: (1) high-dose 1,25(OH)(2)D(3), 0.2 microg/kg (group D(3)-0.2); (2) low-dose 1,25(OH)(2)D(3), 0.04 microg/kg (group D(3)-0.04); (3) high-dose OCT, 0.2 microg/kg (group OCT-0.2); (4) low-dose OCT, 0.04 microg/kg (group OCT-0.04); and (5) ADR-induced nephropathy (group ADR). The death rate at week 20 in group D(3)-0.2 was 50%, significantly higher than the death rates in the other groups, except for group D(3)-0.04 (P <.05). The serum creatinine and blood urea nitrogen levels were the highest in group D(3)-0.2, although the difference was not significant. In contrast, in groups OCT-0.2 and OCT-0.04, tubular changes and interstitial volume were smaller than in groups D(3)-0.2 and D(3)-0.04 (P <.05). Although calcium deposits increased in group D(3)-0.2, the difference was not significant. Glomerular expression of transforming growth factor-beta1 (TGF-beta1) expression was less in groups OCT-0.2 and OCT-0.04 than in groups D(3)-0.2 and D(3)-0.04 (P <.05). Glomerular fibronectin expression was less in group OCT-0.2 than in groups D(3)-0.2 and ADR (P <.05). Tubulointerstitial expression of TGF-beta1 was greater in group D(3)-0.2 than in group ADR and greater in group D(3)-0.04 than in group OCT-0.04 (P <.05). We conclude that a high dose of 1,25(OH)(2)D(3) accelerated the progressive renal deterioration of ADR-induced nephropathy, and, as a result, OCT was able to attenuate renal histologic lesions.

Animals↗
PubMed2002

Reduced p21, p27 and vitamin D receptor in the nodular hyperplasia in patients with advanced secondary hyperparathyroidism.

BACKGROUND: In uremic patients with secondary hyperparathyroidism (2HPT), nodular hyperplasia of parathyroid gland shows a monoclonal pattern of cell proliferation, in which a decreased density of vitamin D receptor (VDR) also is demonstrated. The present study aimed at elucidating the mechanism of parathyroid cell proliferation in relation to cell cycle determinants in patients with advanced 2HPT. METHODS: The expression of cyclin-dependent kinase inhibitors, p21 and p27, and VDR were examined and compared among four groups of nodular (Nd; N = 23) or diffuse (Df; N = 6) hyperplastic parathyroid glands resected due to 2HPT, primary adenomas (Ad; N = 15), and histologically-normal parathyroid glands (C; N = 20) removed during thyroidectomy. Immunohistochemical analyses for VDR, p21, p27 and Ki67 antigen were performed in formalin-fixed paraffin-embedded tissues by using specific polyclonal antibody. The distribution and the intensity of immunoreactivity was quantified by using NIH imaging, and was expressed as the labeling index (LI) of positive nuclear staining in a random set of 1000 cells. RESULTS: p21 LI was significantly diminished in both Nd (85 +/- 110; mean +/- SD) and Ad (136 +/- 122) as compared to that in Df (360 +/- 191) or C (359 +/- 228; P < 0.01). p27 LI was also significantly diminished in both Nd (97 +/- 156) and Ad (187 +/- 196) as compared to that in Df (532 +/- 146) or C (631 +/- 170; P < 0.01). VDR LI in Nd (162 +/- 194) was also significantly lower than that in Df (495 +/- 337), Ad (383 +/- 262), or C (659 +/- 234), respectively (P < 0.01). Parathyroid sections with high nuclear VDR expression elicited high p21 and p27 expression. Both p21 and p27 LI in Nd correlated significantly with nuclear VDR LI (r = 0.92; P < 0.01, r = 0.76; P < 0.01), but not with p53 LI, and inversely correlated with the glandular weight (r = 0.44; P < 0.05, r = 0.41; P < 0.05). CONCLUSIONS: The reduced expression of p21 and p27, in a VDR-dependent manner, is a major pathogenic factor for a nodular parathyroid gland growth.

Adult↗
PubMed2000

Locally activated renin-angiotensin system associated with TGF-beta1 as a major factor for renal injury induced by chronic inhibition of nitric oxide synthase in rats.

Chronic inhibition of nitric oxide synthase (NOS) is known to cause renal parenchymal injury with systemic hypertension. To elucidate the pathogenetic mechanism in renal damage induced by NOS inhibition, N(omega)-nitro-L-arginine methyl ester (L-NAME) was given orally for 12 wk in Wistar rats, and the roles of tissue renin-angiotensin system and transforming growth factor-beta1 (TGF-beta1) were investigated. BP and urinary protein excretion increased significantly in L-NAME rats compared with control rats, and glomerulosclerosis and interstitial fibrosis developed. In L-NAME rats, the cortical tissue levels of angiotensin-converting enzyme activity and angiotensin II were significantly higher than those in control rats. The cortical mRNA expressions of both TGF-beta1 and fibronectin were significantly elevated in L-NAME rats. Immunohistochemically, increased expressions of both fibronectin and alpha-smooth muscle actin were also revealed in L-NAME rats. In L-NAME rats, these histologic injuries and the increased expression of TGF-beta1 were equally ameliorated by either angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist, but not by hydralazine. In conclusion, the locally activated renin-angiotensin system in connection with the increased TGF-beta1 expression is a major pathogenetic feature of renal injury in chronically NOS-inhibited rats.

Actins↗