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 Science / Kyoto University / DFAM

La glomérulonéphrite mésangioproliférative (GNMP) se caractérise par une inflammation locale et la prolifération et l’apoptose des cellules mésangiales (CM). La protéine apparentée à l’hormone parathyroïdienne (PTHrP) a été impliquée dans ces processus dans divers types cellulaires. Nous avons analysé les effets de la PTHrP sur ces processus dans les CM. Nous montrons que la PTHrP majore la prolifération des CM par voie intracrine et diminue leur apoptose par voie paracrine. La PTHrP stimule les voies de l’AMPc/PKA et PI3-K/Akt conduisant à l’activation du NFkB et à la majoration de la cyclooxygénase-2 (Cox-2). La Cox-2 était responsable de la survie des CM par la PTHrP. Par ailleurs, l’IL-1beta et le TNF-alpha majorent l’expression de la PTHrP dans les CM, et la PTHrP elle-même induisait l’expression de cytokines et chimiokines. L’expression des cytokines (IL-17, IL-16), était brève (pic à 2h). L’expression des chimiokine (RANTES, MIP-2, TARC et I-TAC) était plus prolongée (4h). Dans un modèle murin de GNMP, la PTHrP était surexprimée à J1 dans les glomérules malades. Elle pourrait contribuer à l’inflammation locale, à la prolifération et à la survie des CM. / Mesangial proliferative glomerulonephritis (MPGN) is characterized by mesangial cells (MC) inflammation, proliferation and apoptosis. The parathyroid hormone-related protein (PTHrP) is known to influence these processes in many cell types. In this work we analyzed the effects of PTHrP on MC proliferation, apoptosis and inflammation. Our results show that PTHrP induced MC proliferation through the intracrine pathway while it promoted their survival through the paracrine one. PTHrP activating its receptor PTH1R, led to the activation of cAMP/PKA and PI3-K/Akt pathways, which induced NF-kappaB, and upregulated the cyclooxygenase-2 (Cox-2). We have shown that the Cox-2 was responsible of the anti-apoptotic effect of PTHrP on MC. Otherwise, IL-1beta and TNF-alpha importantly upregulated the PTHrP in MC and PTHrP itself led to an overexpression of many cytokines and chemokines. The overexpression of cytokines (IL-17 and IL-16) was brief (2h) while that of chemokines was extended (4h). In a mouse model of MPGN, PTHrP was upregulated in the injured glomeruli at day 1. PTHrP may then contribute to the inflammation, the proliferation and the survival of MC.

<p>Glomerulosclerosis (GS) is the irreversible scarring of glomerular tissue which underlies the development of chronic kidney disease (CKD). Increased intraglomerular capillary pressure (P_gc) is a major contributor to the development of GS and can occur in both hypertensive and diabetic patients. With elevated P_gc, <em>in vitro</em> and <em>in vivo</em> evidence suggest that mesangial cells (MC) experience cyclic stretch and secrete pro-fibrotic factors such as connective tissue growth factor (CTGF) which contributes to GS. The signaling pathways that are activated in response to elevated P_gc and lead to extracellular matrix (ECM) production in MCs are the main focus of this thesis.</p> <p>Previous data demonstrated activation of the Rho GTPase, Rac1, with cyclic stretch in MCs. Furthermore, the most characterized effector of Rac1, p21-activated kinase (PAK), has been observed to have a role in endothelial cells (ECs) exposed to mechanical stress. We thus proposed that the Rac1-PAK signaling pathway is involved in mechanical stress signaling in MCs.</p> <p>Our data demonstrate that Rac1-PAK signaling was activated in response to cyclic stretch and required for stretch-induced CTGF production in MCs. RhoA activation was also regulated by Rac1-PAK signaling, and RhoA/ROCK were observed to mediate CTGF upregulation with stretch. Further investigation on the role of Rac1-PAK signaling and how it regulates CTGF in MCs exposed to stretch, will provide insight into potential therapeutic targets to delay the progression of hypertension-mediated CKD.</p> / Master of Science in Medical Sciences (MSMS)

科学研究費補助金 研究種目:一般研究(B)(2) 課題番号:07457240 研究代表者:宮田 敏男 研究期間:1995-1996年度