A Cancellation Method of Periodic Interference in Pulse-Like Signals Using an Adaptive Filter and Its Application to Flash ERGs

論文「パルス状信号に混入する交流雑音の適応フィルタによる除去法とそのフラッシュ光網膜電位図への適用」（電子情報通信学会論文誌D Vol.J94-D,No.10, pp.1685-1695. 2011 に掲載）の英訳. 許諾番号14RB002

Connective tissue growth factor is correlated with peritoneal lymphangiogenesis.

Lymphatic absorption in the peritoneal cavity may contribute to ultrafiltration failure in peritoneal dialysis (PD). Lymphatic vessels develop during PD-related peritoneal fibrosis. Connective tissue growth factor (CTGF, also called CCN2) is an important determinant of fibrotic tissue remodeling, but little is known about its possible involvement in lymphangiogenesis. In this study, we investigated the relationship between CTGF and peritoneal lymphangiogenesis. A positive correlation was observed between vascular endothelial growth factor-C (VEGF-C), a major lymphangiogenic growth factor, and the CTGF concentration in human PD effluents. CTGF expression was positively correlated with expression of lymphatic markers and VEGF-C in human peritoneal biopsies. We found a positive correlation between the increase in CTGF and the increase in VEGF-C in cultured human peritoneal mesothelial cells (HPMCs) treated with transforming growth factor-β1 (TGF-β1). The diaphragm is a central player in peritoneal lymphatic absorption. CTGF expression was also correlated with expression of VEGF-C and lymphatics in a rat diaphragmatic fibrosis model induced by chlorhexidine gluconate (CG). Furthermore, CTGF gene deletion reduced VEGF-C expression and peritoneal lymphangiogenesis in the mouse CG model. Inhibition of CTGF also reduced VEGF-C upregulation in HPMCs treated with TGF-β1. Our results suggest a close relationship between CTGF and PD-associated lymphangiogenesis

TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2

Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of most cases of ALS, the molecular mechanism and the in vivo relation of ALS dyslipidemia with TDP-43 have been unclear. To analyze the dyslipidemia-related gene expression by TDP-43, we performed expression microarray and RNA deep sequencing (RNA-Seq) using cell lines expressing high levels of TDP-43 and identified 434 significantly altered genes including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. Elevated TDP-43 impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis. The amount of cholesterol was significantly decreased in the spinal cords of TDP-43-overexpressed ALS model mice and in the cerebrospinal fluids of ALS patients. These results suggested that TDP-43 could play an essential role in cholesterol biosynthesis in relation to ALS dyslipidemia

Increase of Total Nephron Albumin Filtration and Reabsorption in Diabetic Nephropathy

There is a hot debate concerning actual amount of albumin filtered through glomeruli and reabsorbed at proximal tubules in normal kidneys and diabetic conditions. To overcome current technical problems, we generated a drug-inducible megalin knockout mouse line, megalin(lox/lox);Ndrg1-CreER[T2] (or iMegKO), whose protein reabsorption can be shut off anytime by tamoxifen (Tam). After Tam administration, renal megalin protein expression was reduced by 92% compared to wild-type C57BL/6J mice, and renal reabsorption of intravenously-injected retinol binding protein was almost completely abrogated. Urinary albumin excretion increased to 175 μg/day (0.460 mg/mg-creatinine), suggesting that this was the amount of total nephron albumin filtration. Glomerular sieving coefficient of albumin was 1.7 x 10[-5]. By comparing streptozotocin-induced, Tam-treated, diabetic STZ;iMegKO mice with non-STZ;iMegKO mice, we estimated that daily albumin filtration was increased by 1.9-fold, reabsorption was increased by 1.8-fold, and reabsorption efficiency was reduced to 86% by development of diabetes (versus 96% in control). Such abnormalities were well normalized after insulin treatment. Another type 1 diabetic model of Akita;iMegKO mice showed equivalent results. This study reveals actual values and changes of albumin filtration and reabsorption in early diabetic nephropathy, bringing new insights into our understanding of renal albumin dynamics in hyperfiltration status of diabetic nephropath

Natriuretic peptide receptor guanylyl cyclase-A pathway counteracts glomerular injury evoked by aldosterone through p38 mitogen-activated protein kinase inhibition

Guanylyl cyclase-A (GC-A) signaling, a natriuretic peptide receptor, exerts renoprotective effects by stimulating natriuresis and reducing blood pressure. Previously we demonstrated massive albuminuria with hypertension in uninephrectomized, aldosterone-infused, and high salt-fed (ALDO) systemic GC-A KO mice with enhanced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in podocytes. In the present study, we examined the interaction between p38 MAPK and GC-A signaling. The administration of FR167653, p38 MAPK inhibitor, reduced systolic blood pressure (SBP), urinary albumin excretion, segmental sclerosis, podocyte injury, and apoptosis. To further investigate the local action of natriuretic peptide and p38 MAPK in podocytes, we generated podocyte-specific (pod) GC-A conditional KO (cKO) mice. ALDO pod GC-A cKO mice demonstrated increased urinary albumin excretion with marked mesangial expansion, podocyte injury and apoptosis, but without blood pressure elevation. FR167653 also suppressed urinary albumin excretion without reducing SBP. Finally, we revealed that atrial natriuretic peptide increased phosphorylation of MAPK phosphatase-1 (MKP-1) concomitant with inhibited phosphorylation of p38 MAPK in response to MAPK kinase 3 activation, thereby resulting in decreased mRNA expression of the apoptosis-related gene, Bax, and Bax/Bcl2 ratio in cultured podocytes. These results indicate that natriuretic peptide exerts a renoprotective effect via inhibiting phosphorylation of p38 MAPK in podocytes.</p

Structure of Musashi1 in a complex with target RNA: the role of aromatic stacking interactions

Mammalian Musashi1 (Msi1) is an RNA-binding protein that regulates the translation of target mRNAs, and participates in the maintenance of cell ‘stemness’ and tumorigenesis. Msi1 reportedly binds to the 3′-untranslated region of mRNA of Numb, which encodes Notch inhibitor, and impedes initiation of its translation by competing with eIF4G for PABP binding, resulting in triggering of Notch signaling. Here, the mechanism by which Msi1 recognizes the target RNA sequence using its Ribonucleoprotein (RNP)-type RNA-binding domains (RBDs), RBD1 and RBD2 has been revealed on identification of the minimal binding RNA for each RBD and determination of the three-dimensional structure of the RBD1:RNA complex. Unique interactions were found for the recognition of the target sequence by Msi1 RBD1: adenine is sandwiched by two phenylalanines and guanine is stacked on the tryptophan in the loop between β1 and α1. The minimal recognition sequences that we have defined for Msi1 RBD1 and RBD2 have actually been found in many Msi1 target mRNAs reported to date. The present study provides molecular clues for understanding the biology involving Musashi family proteins

マウス抗糸球体基底膜抗体腎炎におけるメサンギウム細胞由来結合組織成長因子の重要な役割に関する研究

京都大学0048新制・課程博士博士(医学)甲第21013号医博第4359号新制||医||1028(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 長船 健二, 教授 瀬原 淳子, 教授 小川 修学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

The Successful Treatment of a Case of HCV-associated Cryoglobulinemic Glomerulonephritis with Rituximab, Direct-acting Antiviral Agents, Plasmapheresis and Long-term Steroid Despite Serologically Persistent Cryoglobulinemia

Novel treatments with rituximab or direct-acting antiviral agents (DAAs) were expected to improve the clinical outcomes of hepatitis C virus (HCV)-associated cryoglobulinemia in the last decade. Recently, however, persistent cases of cryoglobulinemia have been reported, and the ideal approach to treating such cases has not been established. We herein report a case of the successful treatment of HCV-associated cryoglobulinemic glomerulonephritis with rituximab, DAAs, occasional plasmapheresis and long-term steroid, with the patient's renal function and proteinuria improving over the long term despite serologically persistent cryoglobulinemia. This case suggests the efficacy of combination treatment with rituximab, DAAs, occasional plasmapheresis and long-term steroid for persistent cryoglobulinemia

CTGF in kidney fibrosis and glomerulonephritis

Abstract Background Glomerulonephritis, which causes inflammation in glomeruli, is a common cause of end-stage renal failure. Severe and prolonged inflammation can damage glomeruli and lead to kidney fibrosis. Connective tissue growth factor (CTGF) is a member of the CCN matricellular protein family, consisting of four domains, that regulates the signaling of other growth factors and promotes kidney fibrosis. Main body of the abstract CTGF can simultaneously interact with several factors with its four domains. The microenvironment differs depending on the types of cells and tissues and differentiation stages of these cells. The diverse biological actions of CTGF on various types of cells and tissues depend on this difference in microenvironment. In the kidney, CTGF is expressed at low levels in normal condition and its expression is upregulated by kidney fibrosis. CTGF expression is known to be upregulated in the extra-capillary and mesangial lesions of glomerulonephritis in human kidney biopsy samples. In addition to involvement in fibrosis, CTGF modulates the expression of inflammatory mediators, including cytokines and chemokines, through distinct signaling pathways, in various cell systems. In anti-glomerular basement membrane (GBM) glomerulonephritis, systemic CTGF knockout (Rosa-CTGF cKO) mice exhibit 50% reduction of proteinuria and decreased crescent formation and mesangial expansion compared with control mice. In addition to fibrotic markers, the glomerular mRNA expression of Ccl2 is increased in the control mice with anti-GBM glomerulonephritis, and this increase is reduced in Rosa-CTGF cKO mice with nephritis. Accumulation of MAC2-positive cells in glomeruli is also reduced in Rosa-CTGF cKO mice. These results suggest that CTGF may be required for the upregulation of Ccl2 expression not only in anti-GBM glomerulonephritis but also in other types of glomerulonephritis, such as IgA nephropathy; CTGF expression and accumulation of macrophages in the mesangial area have been documented in these glomerular diseases. CTGF induces the expression of inflammatory mediators and promotes cell adhesion. Short conclusion CTGF plays an important role in the development of glomerulonephritis by inducing the inflammatory process. CTGF is a potentiate target for the treatment of glomerulonephritis