Celecoxib inhibits growth of human autosomal dominant polycystic kidney cyst-lining epithelial cells through the VEGF/Raf/MAPK/ERK signaling pathway.
Celecoxib inhibits growth of human autosomal dominant polycystic kidney cyst-lining epithelial cells through the VEGF/Raf/MAPK/ERK signaling pathway.
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塞来昔布通过 VEGF/Raf/MAPK/ERK 信号通路抑制人常染色体显性多囊肾囊肿衬里上皮细胞的生长
DOI：
10.1007/s11033-012-1611-2
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发表时间：
2012-07
影响因子：
2.8
通讯作者：
Mei CL
中科院分区：
文献类型：
--
作者：
Xu T;Wang NS;Fu LL;Ye CY;Yu SQ;Mei CL
常染色体显性遗传性多囊肾病(ADPKD)是一种进行性慢性肾脏疾病。到目前为止，还没有有效的药物来阻止包囊的发展和增长。在本研究中，我们探索了环氧合酶-2特异性抑制剂塞来昔布(CXB)对原代培养的人ADPKD囊衬里上皮细胞的新作用。原代培养的ADPKD囊壁上皮细胞取自5例患者。用不同方法检测CXB对体外培养细胞BrdU掺入、细胞凋亡和增殖的影响。观察补肾活血方对实验性肾功能不全大鼠肾脏重量、囊性指数、纤维化指数、血尿素氮(BUN)、血肌酐(Scr)、6-酮-前列腺素F-1(6-keto-PGF1)α、血栓素2(TXB_2)及肾组织增殖细胞核抗原表达的影响。CXB以时间和剂量依赖的方式抑制ADPKD囊肿衬里上皮细胞的增殖，阻断细胞释放血管内皮生长因子，并诱导广泛的细胞凋亡。此外，CXB还上调了细胞周期负调控因子p21CIP/WAF1和细胞周期正调控因子Cyclin A，阻断了ERK1/2的磷酸化，诱导了细胞凋亡因子Bax和caspase-3的表达，降低了Bcl2的表达。此外，CXB还可抑制ADPKD囊肿衬里上皮细胞VEGFR-2和Raf-1的表达。能显著降低HAN：SPRD大鼠的囊性指数、纤维化指数、白细胞数、BUN、Scr、6-keto-PGF-1α、TXB_2和肾组织增殖细胞核抗原表达。我们首次证明CXB在体外和体内都能抑制HAN：SPRD大鼠的肾囊壁生长。CXB通过抑制VEGF/VEGFR-2/Raf-1/MAPK/ERK信号通路，抑制ADPKD囊肿衬里上皮细胞的增殖，抑制细胞周期进程，诱导细胞凋亡。
Autosomal dominant polycystic kidney disease (ADPKD) is a progressive chronic kidney disease. To date there are no effective medicines to halt development and growth of cysts. In the present study, we explored novel effects of celecoxib (CXB), a COX-2 specific inhibitor, on primary cultures of human ADPKD cyst-lining epithelial cells. Primary cultures of ADPKD cyst-lining epithelial cells were obtained from five patients. Effects of CXB were measured by various assays to detect BrdU incorporation, apoptosis and proliferation in vitro. Additionally, effects of CXB on kidney weight, the cyst index, the fibrosis index, blood urea nitrogen (BUN), serum creatinine (SCr), serum 6-keto-PGF-1α, serum thromboxane-2 (TXB2) and renal PCNA expression were assessed in Han:SPRD rat, a well-characterized rodent model of PKD. CXB inhibited proliferation of ADPKD cyst-lining epithelial cells, blocked the release of VEGF from the cells and induced extensive apoptosis in a time- and dose-dependent manner. Moreover, CXB up-regulated the cell cycle negative regulator p21CIP/WAF1and the cell cycle positive regulator Cyclin A, blocked ERK1/2 phosphorylation, induced apoptotic factors (Bax and caspase-3) and reduced Bcl-2. Furthermore, CXB inhibited the expression of VEGFR-2 and Raf-1 in ADPKD cyst-lining epithelial cells. CXB markedly reduced the cyst index, the fibrosis index, leukocyte infiltration, BUN, SCr, serum 6-keto-PGF-1α, TXB2 and renal PCNA expression in Han:SPRD rat. We demonstrated for the first time that CXB could suppress renal cyst-lining growth both in vitro and in vivo in Han:SPRD rat. CXB can inhibit proliferation, suppress cell cycle progression, and induce apoptosis in ADPKD cyst-lining epithelial cells through the inhibition of the VEGF/VEGFR-2/Raf-1/MAPK/ERK signaling pathway.
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影响因子：
45.3
作者：
Antonarakis, Emmanuel S.;Heath, Elisabeth I.;Carducci, Michael A.
通讯作者：
Carducci, Michael A.
影响因子：
11.2
作者：
Correale, Jorge;Villa, Andres
通讯作者：
Villa, Andres
影响因子：
3
作者：
Krzyzanowska, Monika K.;Tannock, Ian F.;Bjarnason, Georg A.
通讯作者：
Bjarnason, Georg A.
影响因子：
5.7
作者：
Juan-Zhang;Bian, Hong-Jun;Ji, Xiao-Ping
通讯作者：
Ji, Xiao-Ping
影响因子：
6.2
作者：
Rini, BI;Weinberg, V;Small, EJ
通讯作者：
Small, EJ