Activation of NFKB-JMJD3 signaling promotes bladder fibrosis via boosting bladder smooth muscle cell proliferation and collagen accumulation
Activation of NFKB-JMJD3 signaling promotes bladder fibrosis via boosting bladder smooth muscle cell proliferation and collagen accumulation
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NFKB-JMJD3 信号的激活通过促进膀胱平滑肌细胞增殖和胶原蛋白积累促进膀胱纤维化
DOI：
10.1016/j.bbadis.2019.05.008
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发表时间：
2019-09-01
影响因子：
6.2
通讯作者：
Ai, Jianzhong
中科院分区：
文献类型：
--
作者：
Lai, Junyu;Ge, Manqing;Ai, Jianzhong
慢性膀胱炎的特征在于膀胱壁的增生和纤维化以及膀胱的减弱的顺应性。为了进一步阐明其潜在的分子机制，研究了NF κ B-JMJD 3信号通路在膀胱炎诱导的膀胱纤维化中的作用。在通过腹腔注射环磷酰胺（cyclophosphamide，CTX）建立的膀胱炎小鼠模型中检测Jmjd 3和Col 1/3的表达。采用脂多糖（LPS）刺激体外培养的人膀胱平滑肌细胞（hBSMCs），采用EdU、CCK 8、流式细胞术、qPCR、western blotting和免疫荧光等方法检测细胞增殖和胶原合成。此外，分别使用其选择性拮抗剂JSH 23和GSK-J 4研究NF κ B和JM JD 3对细胞增殖和胶原积累的影响。膀胱炎组膀胱肌细胞Jmjd 3、Col 1和Col 3的表达明显增加。LPS刺激可显著激活NF-κ B B信号通路，上调JM JD 3的表达，NF-κ B-JM JD 3信号通路的激活分别通过上调CCND 1和COL 1/3的表达，促进hBSMCs增殖和胶原积累。我们的研究揭示了NF κ B-JMJD 3信号通过调节hBSMC增殖和细胞外基质（ECM）沉积在膀胱炎诱导的膀胱重建中的关键作用，这些发现为膀胱炎患者的有效治疗提供了途径。
Chronic cystitis is characterized by the hyperplasia and fibrosis of the bladder wall as well as attenuated compliance of the bladder. To further unravel its underlying molecular mechanism, the role of NF kappa B-JMJD3 signaling pathway in cystitis induced bladder fibrosis was investigated. Jmjd3 and Col1/3 expression was detected in a cystitis mouse model that was developed by intraperitoneal injection of cyclophosphamide (CYP). Human bladder smooth muscle cells (hBSMCs) were stimulated in vitro with lipopolysaccharide (LPS), and the cell proliferation and collagen accumulation were detected using EdU, CCK8, flow cytometry, qPCR, western blotting and immunofluorescence assays. Furthermore, the effects of NF kappa B and JMJD3 on cell proliferation and collagen accumulation were investigated using its selective antagonists, JSH23 and GSK-J4, respectively. CYP induced cystitis significantly increased Jmjd3, Col1 and Col3 expression in the bladder muscle cells. Furthermore, LPS stimulation markedly activated NF kappa B signaling and elevated JMJD3 expression in hBSMCs, and the activation of NF kappa B-JMJD3 signaling significantly promoted cell proliferation and collagen accumulation by upregulating CCND1 and COL1/3 expression, respectively. Our study reveals the critical role of NF kappa B-JMJD3 signaling in cystitis induced bladder reconstruction by regulating hBSMC proliferation and extracellular matrix (ECM) deposition, and these findings provide an avenue for effective treatment of patients with cystitis.