Smad1の条件付き遺伝子削除は進行性糸球体腎炎による糸球体傷害を改善する

Matrix expansion and cell proliferation are concomitantly observed in various glomerular injuries. However, the molecular mechanisms responsible for these changes have not been fully elucidated. We have reported that Smad1 is a key signalling molecule that regulates the transcription of type IV collagen (Col4) in mesangial matrix expansion and is thereby involved in glomerular injury in an acute model of glomerulonephritis. In this study, we addressed the role of Smad1 signalling in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis, using conditional deletion of Smad1 in Rosa26CreERT2 mice (Smad1-CKO). Mesangial matrix expansion in the Smad1-CKO mice with NTN was significantly inhibited compared with that in wild type mice with NTN, which was consistent with the decrease in Col4 expression level. On the other hand, STAT3 activation and cell proliferation were not influenced by Smad1 deletion in the NTN model. Therefore, we investigated another factor that activates cell proliferation in the absence of Smad1. Id2 induced VEGF secretion and subsequent STAT3 activation, independently of Smad1 expression in mouse mesangial cells. Here we show that Smad1 plays an important role in the development of glomerular injury without affecting cell proliferation, in progressive glomerulonephritis

Conditional Deletion of Smad1 Ameliorates Glomerular Injury in Progressive Glomerulonephritis

Matrix expansion and cell proliferation are concomitantly observed in various glomerular injuries. However, the molecular mechanisms responsible for these changes have not been fully elucidated. We have reported that Smad1 is a key signalling molecule that regulates the transcription of type IV collagen (Col4) in mesangial matrix expansion and is thereby involved in glomerular injury in an acute model of glomerulonephritis. In this study, we addressed the role of Smad1 signalling in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis, using conditional deletion of Smad1 in Rosa26CreERT2 mice (Smad1-CKO). Mesangial matrix expansion in the Smad1-CKO mice with NTN was significantly inhibited compared with that in wild type mice with NTN, which was consistent with the decrease in Col4 expression level. On the other hand, STAT3 activation and cell proliferation were not influenced by Smad1 deletion in the NTN model. Therefore, we investigated another factor that activates cell proliferation in the absence of Smad1. Id2 induced VEGF secretion and subsequent STAT3 activation, independently of Smad1 expression in mouse mesangial cells. Here we show that Smad1 plays an important role in the development of glomerular injury without affecting cell proliferation, in progressive glomerulonephritis

Activation of Src Mediates PDGF-Induced Smad1 Phosphorylation and Contributes to the Progression of Glomerulosclerosis in Glomerulonephritis

Platelet-derived growth factor (PDGF) plays critical roles in mesangial cell (MC) proliferation in mesangial proliferative glomerulonephritis. We showed previously that Smad1 contributes to PDGF-dependent proliferation of MCs, but the mechanism by which Smad1 is activated by PDGF is not precisely known. Here we examined the role of c-Src tyrosine kinase in the proliferative change of MCs. Experimental mesangial proliferative glomerulonephritis (Thy1 GN) was induced by a single intravenous injection of anti-rat Thy-1.1 monoclonal antibody. In Thy1 GN, MC proliferation and type IV collagen (Col4) expression peaked on day 6. Immunohistochemical staining for the expression of phospho-Src (pSrc), phospho-Smad1 (pSmad1), Col4, and smooth muscle α-actin (SMA) revealed that the activation of c-Src and Smad1 signals in glomeruli peaked on day 6, consistent with the peak of mesangial proliferation. When treated with PP2, a Src inhibitor, both mesangial proliferation and sclerosis were significantly reduced. PP2 administration also significantly reduced pSmad1, Col4, and SMA expression. PDGF induced Col4 synthesis in association with increased expression of pSrc and pSmad1 in cultured MCs. In addition, PP2 reduced Col4 synthesis along with decreased pSrc and pSmad1 protein expression in vitro. Moreover, the addition of siRNA against c-Src significantly reduced the phosphorylation of Smad1 and the overproduction of Col4. These results provide new evidence that the activation of Src/Smad1 signaling pathway plays a key role in the development of glomerulosclerosis in experimental glomerulonephritis

Protein inhibitor of activated STAT、PIASyはメサンギウム細胞においてE12と共役しα-SMAの発現を制御する。

京都大学0048新制・課程博士博士(医学)甲第17459号医博第3802号新制||医||998(附属図書館)30225京都大学大学院医学研究科医学専攻(主査)教授 萩原 正敏, 教授 岩井 一宏, 教授 小川 修学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Estimating annual individual doses for evacuees returning home to areas affected by the Fukushima nuclear accident

To contribute to the reconstruction and revitalization of Fukushima Prefecture following the 2011 nuclear power disaster, annual individual doses were estimated for evacuees who will re- turn home to Tamura City, Kawauchi Village, and Iitate Village in Fukushima. Ambient external dose rates and individual doses obtained with personal dosimeters were measured at many residen- tial and occupational sites throughout the study areas to obtain fun- damental data needed for the estimation. The measurement results indicated that the ratio of individual dose based on a personal dosimeter to the ambient external dose measurement was 0.7 with 10% uncertainty. Multiplying the ambient external dose by 0.7 may be an appropriate measure of the effective dose to an individ- ual in the investigated area. Annual individual doses were estimated for representative lifestyles and occupations based on the ambi- ent external dose rates at the measurement sites, taking into ac- count the relationship between the ambient external dose andindividual dose. The results were as follows: 0.6–2.3 mSv y−1in Tamura, 1.1–5.5 mSv y−1 in Kawauchi, and 3.8–17 mSv y−1 in Iitate. For all areas investigated, the estimated dose to out- door workers was higher than that to indoor workers. Identifying ways to reduce the amount of time that an outdoor worker spends outdoors would provide an effective measure to reduce dose

Katholikon des Klosters Shën Mëria

Kuppel mit Christusbild, umgeben von EngelnHauptkirche des Marienklosters, Hl. Maria Der Grundriss ist völlig verzogen, er weist keinen einzigen rechten Winkel auf.Galina Fingarova (DiFaB) (http://difab.univie.ac.at/