Acidic organelles mediate TGF-β1-induced cellular fibrosis via (pro)renin receptor and vacuolar ATPase trafficking in human peritoneal mesothelial cells.
Acidic organelles mediate TGF-β1-induced cellular fibrosis via (pro)renin receptor and vacuolar ATPase trafficking in human peritoneal mesothelial cells.
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DOI：
10.1038/s41598-018-20940-x
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发表时间：
2018-02-08
影响因子：
4.6
通讯作者：
Ito S
中科院分区：
文献类型：
--
作者：
Oba-Yabana I;Mori T;Takahashi C;Hirose T;Ohsaki Y;Kinugasa S;Muroya Y;Sato E;Nguyen G;Piedagnel R;Ronco PM;Totsune K;Ito S
TGF-β1可通过空泡型H+-ATP酶（V-ATP酶）介导的途径引起肾小管损伤，由葡萄糖降解产物甲基乙二醛诱导产生腹膜损伤和纤维化。本研究调查了 V-ATP 酶及其辅助蛋白（肾素原受体）在腹膜透析期间腹膜纤维化中的作用。每天腹膜内给予20mM甲基乙二醛的大鼠在7天后出现明显的腹膜纤维化，同时TGF-β和V-ATP酶的表达增加，而同时给予100mM巴弗洛霉素A1抑制V-ATP酶可降低腹膜纤维化。肾素（原）受体和V-ATP酶在人腹膜间皮细胞的酸性细胞器和细胞膜中表达。 TGF-β1 上调胶原蛋白、α-SMA 和 EDA-纤连蛋白的表达，以及 ERK1/2 磷酸化，而 ERK1/2 磷酸化可通过抑制 V-ATP 酶、肾素原受体或 MAPK 途径而降低。纤连蛋白和可溶性肾素（原）受体通过响应 TGF-β1 的酸性细胞器运输从细胞中排出； V-ATP酶的抑制也抑制了这种排泄。接受腹膜透析的患者流出物中可溶性肾素（原）受体浓度与透析液与血浆中肌酐的比率相关。总之，这些结果证明了通过腹膜间皮细胞酸性细胞器中肾素（原）受体和 V-ATP 酶的新型纤维化机制。
TGF-β1, which can cause renal tubular injury through a vacuolar-type H+-ATPase (V-ATPase)-mediated pathway, is induced by the glucose degradation product methylglyoxal to yield peritoneal injury and fibrosis. The present study investigated the roles of V-ATPase and its accessory protein, the (pro)renin receptor, in peritoneal fibrosis during peritoneal dialysis. Rats daily administered 20 mM methylglyoxal intraperitoneally developed significant peritoneal fibrosis after 7 days with increased expression of TGF-β and V-ATPase, which was reduced by the inhibition of V-ATPase with co-administration of 100 mM bafilomycin A1. The (pro)renin receptor and V-ATPase were expressed in acidic organelles and cell membranes of human peritoneal mesothelial cells. TGF-β1 upregulated the expression of collagens, α-SMA, and EDA-fibronectin, together with ERK1/2 phosphorylation, which was reduced by inhibition of V-ATPase, (pro)renin receptor, or the MAPK pathway. Fibronectin and the soluble (pro)renin receptor were excreted from cells by acidic organelle trafficking in response to TGF-β1; this excretion was also suppressed by inhibition of V-ATPase. Soluble (pro)renin receptor concentrations in effluents of patients undergoing peritoneal dialysis were associated with the dialysate-to-plasma ratio of creatinine. Together, these results demonstrate a novel fibrosis mechanism through the (pro)renin receptor and V-ATPase in the acidic organelles of peritoneal mesothelial cells.
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影响因子：
--
作者：
Hirose, Takuo;Mori, Nobuyoshi;Imai, Yutaka
通讯作者：
Imai, Yutaka
DOI：
10.1152/ajprenal.00278.2011
发表时间：
2012-05-01
影响因子：
4.2
作者：
Cao, Xueqin;Yang, Qiongqiong;Yu, Xueqing
通讯作者：
Yu, Xueqing
影响因子：
8.3
作者：
Cousin, Christelle;Bracquart, Diane;Nguyen, Genevieve
通讯作者：
Nguyen, Genevieve
影响因子：
13.2
作者：
Davies, Simon J.
通讯作者：
Davies, Simon J.
影响因子：
56.9
作者：
Cruciat, Cristina-Maria;Ohkawara, Bisei;Niehrs, Christof
通讯作者：
Niehrs, Christof