A Novel Diabetes Mellitus Mouse Model MAFA-Deficient and Beta Cell-Specific MAFK-Overexpressing Hybrid Transgenic Mice Developed Severe Diabetic Nephropathy and Improved with TCV-116 (Candesartan Cilexetil) Treatment

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転写因子異常による巣状糸球体硬化症発症機序の解明

科学研究費助成事業 研究成果報告書：基盤研究(C)2015-2017課題番号 : 15K0924

Prevention of diabetic nephropathy by MafB

課題番号：2059094

Anaemia is an essential complication of ANCA-associated renal vasculitis: a single center cohort study

BackgroundAnaemia is a common complication of patients with antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis. Nevertheless, the cause and degree of such cases of anaemia have not been elucidated in detail. We aimed to investigate the prevalence, cause, pathogenesis of anaemia and the impact of anaemia on prognosis in patients with ANCA-associated renal vasculitis.MethodsWe identified 45 patients with ANCA-associated renal vasculitis that were clinically and/or histologically diagnosed and treated from 2003 to 2014 at University of Tsukuba Hospital. The relationships between anaemia and various clinicopathological findings were evaluated.ResultsAt the time of diagnosis of ANCA-associated renal vasculitis, all patients showed anaemia, with a mean haemoglobin level of 7.5 ± 1.3 g/dL. Renal anaemia was diagnosed in 92% of patients, anaemia of chronic disease (ACD) in 56%, and anaemia due to hemorrhage in 20%. Next, the patients were divided into two groups according to anaemia severity: minimum haemoglobin (min Hb) < 7.5 (n = 24) and min Hb ≥ 7.5 (n = 21). A comparison of baseline characteristics showed that serum albumin, maximum serum creatinine, minimum estimated glomerular filtration rate (eGFR), serum cystatin C, and the area of tubulointerstitial damage were significantly different between the haemoglobin groups (p <  0.05). No significant intergroup differences were observed in iron-related or inflammation-related data. With regard to the relationship between anaemia severity and prognosis, patients in the min Hb < 7.5 group tended to have a lower eGFR. Anaemia severity was associated with markedly lower survival (Log-rank test, p = 0.03).ConclusionsIn this cohort of patients with ANCA-associated renal vasculitis, all subjects exhibited anaemia. In regard to the cause and pathogenesis, the most prevalent form of anaemia was renal anaemia, not ACD, and a potential reason for the high prevalence of anaemia in our cohort may have been the interaction between renal anaemia and ACD. Moreover, anaemia severity was significantly associated with the degree of renal dysfunction and life prognosis

Renal Hemodynamic and Functional Changes in Patients with ADPKD

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A Novel Transgenic Mouse Model of the Human Multiple Myeloma Chromosomal Translocation t(14;16)(q32;q23)

Abstract Multiple myeloma (MM) is a currently incurable neoplasm of terminally differentiated B cells. The translocation and/or overexpression of c-MAF have been observed in human MM. Although c-MAF might function as an oncogene in human MM, there has been no report thus far describing the direct induction of MM by c-MAF overexpression in vivo. In this study, we have generated transgenic (TG) mice that express c-Maf specifically in the B-cell compartment. Aged c-Maf TG mice developed B-cell lymphomas with some clinical features that resembled those of MM, namely, plasma cell expansion and hyperglobulinemia. Quantitative RT-PCR analysis demonstrated that Ccnd2 and Itgb7, which are known target genes of c-Maf, were highly expressed in the lymphoma cells. This novel TG mouse model of the human MM t(14;16)(q32;q23) chromosomal translocation should serve to provide new insight into the role of c-MAF in tumorigenesis. Cancer Res; 71(2); 339–48. ©2011 AACR.</jats:p

MafA-deficient and beta cell-specific MafK-overexpressing hybrid transgenic mice develop human-like severe diabetic nephropathy

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Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels

Nrf2 is a basic leucine zipper transcriptional activator that is essential for the coordinate transcriptional induction of various antioxidant drug-metabolizing enzymes. Numerous studies have firmly established Nrf2\u27s importance in protection from oxidative stress and certain chemical insults. Given the protective function of Nrf2, surprisingly few studies have focused on the relationship between Nrf2 and apoptosis. Therefore, we analysed how Nrf2 influences Fas signaling using Nrf2-deficient T cells. At a concentration of 1 mug/ml, the anti-Fas antibody induced 60% of cell death in Nrf2-deficient cultured thymocytes while, using the same treatment, only 40% of Nrf2 wild-type thymocytes died (P<0.05). Nrf2 deficiency enhances the sensitivity of Fas-mediated apoptosis in T cells. Next we examined the effect of Nrf2 deficiency during hepatocellular apoptosis in vivo. In comparison to wild-type mice, Nrf2-deficient mice displayed more severe hepatitis after induction with the anti-Fas antibody or tumor necrosis factor (TNF)-alpha. The enhanced sensitivity to anti-Fas or TNF-alpha stimulation was restored by preadministration of glutathione ethyl monoester, a compound capable of passing the cell membrane and upregulating the intracellular levels of glutathione. The results indicated that Nrf2 activity regulates the sensitivity of death signals by means of intracellular glutathione levels

A Novel Transgenic Mouse Model of the Human Multiple Myeloma Chromosomal Translocation t(14;16)(q32;q23)

Multiple myeloma (MM) is a currently incurable neoplasm of terminally differentiated B cells. The translocation and/or overexpression of c-MAF have been observed in human MM. Although c-MAF might function as an oncogene in human MM, there has been no report thus far describing the direct induction of MM by c-MAF overexpression in vivo. In this study, we have generated transgenic (TG) mice that express c-Maf specifically in the B-cell compartment. Aged c-Maf TG mice developed B-cell lymphomas with some clinical features that resembled those of MM, namely, plasma cell expansion and hyperglobulinemia. Quantitative RT-PCR analysis demonstrated that Ccnd2 and Itgb7, which are known target genes of c-Maf, were highly expressed in the lymphoma cells. This novel TG mouse model of the human MM t(14;16)(q32;q23) chromosomal translocation should serve to provide new insight into the role of c-MAF in tumorigenesis

The detection of carotid plaque rupture caused by intraplaque hemorrhage by serial high-resolution magnetic resonance imaging: a case report.

BACKGROUND: Plaque rupture is believed to be a critical event that leads to thromboembolic complications in atherosclerotic carotid artery disease. Intraplaque hemorrhage can also cause fibrous cap disruption and may be related to the progression of atherosclerosis. However, the mechanism that leads to fibrous cap disruption is not well defined, and there have been few reports in the literature that carotid plaque rupture could be clearly visualized by serial high-resolution MRI. CASE DESCRIPTION: We describe a case of a 79-year-old man who presented with minor ischemic stroke. On diffusion-weighted image, new multiple embolic spots were detected. Plaque rupture caused by intraplaque hemorrhage could be clearly detected by serial high-resolution MRI of the cervical carotid artery. The patient underwent carotid endarterectomy, and an atheromatous plaque was extracted intact for histologic analysis. In the histologic section corresponding to the MRI slices, plaque rupture caused by intraplaque hemorrhage was demonstrated. CONCLUSIONS: This case represents a valuable example of artery-to-artery embolisms from a carotid plaque rupture secondary to intraplaque hemorrhage. High-resolution MRI may have important applications in natural history studies and in clinical trials of carotid plaques