The lonidamine derivative H2-gamendazole reduces cyst formation in polycystic kidney disease.
The lonidamine derivative H2-gamendazole reduces cyst formation in polycystic kidney disease.
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孤胺衍生物H2-gamendazole降低了多囊性肾脏疾病中的囊肿形成。
DOI：
10.1152/ajprenal.00095.2022
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发表时间：
2022-10-01
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影响因子：
--
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中科院分区：
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常染色体显性遗传性多囊肾病(ADPKD)是一种治疗选择有限的衰弱肾脏肿瘤疾病。它的特点是通过细胞异常增殖形成大量充满液体的囊腔，并由cAMP依赖的Cl-−分泌驱动囊腔充盈液体的分泌。我们利用ADPKD的体外和体内模型，测试了吲哚甲酸H2-甘露醇(H2-GMZ)的有效性，该化合物是一种氯硝胺的衍生物。H2-GMZ能快速阻断Forsklin诱导的人ADPKD细胞的短路电流，并显著抑制cAMP和表皮生长因子诱导的ADPKD细胞的增殖。经H2-GMZ处理的ADPKD细胞的Western印迹分析显示，ERK的磷酸化水平降低，视网膜母细胞瘤的过度磷酸化水平降低。H2-GMZ还降低了ErbB2、Akt和细胞周期蛋白依赖性蛋白4，与热休克蛋白90的抑制一致，并降低了囊性纤维化跨膜电导调节因子CL−通道蛋白的水平。H2-GMZ处理的ADPKD细胞含有更多的小细胞，片状脂膜减少，胞浆肌动蛋白染色减少，即使在低H2-GMZ浓度下也不能完成伤口闭合，这与肌动蛋白细胞骨架的改变和细胞活力降低是一致的。用小鼠后肾器官培养的实验表明，H2-GMZ抑制cAMP刺激的囊泡生长和增大。在体内，H2-GMZ能有效地延缓Pkd1/Flox：Pkhd1-Cre小鼠模型的出生后囊性形成和肾脏增大。因此，H2-GMZ处理降低了Cl-−的分泌、细胞的增殖、细胞的运动和包囊的生长。这些特性，以及已报道的低毒性，表明H2-GMZ可能是治疗ADPKD的一个有吸引力的候选药物。新发现的常染色体显性遗传性多囊肾病是一种肾脏肿瘤性疾病，其特征是肾小管上皮细胞异常增殖形成大量充满液体的囊腔，并由cAMP依赖的Cl-−分泌驱动囊腔充液分泌。本研究表明，氯硝胺衍生物H2-GMZ抑制−分泌、细胞增殖和囊泡生长，提示其可能对ADPKD有治疗价值。
Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder with limited treatment options. It is characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl− secretion. We tested the effectiveness of the indazole carboxylic acid H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes using in vitro and in vivo models of ADPKD. H2-GMZ was effective in rapidly blocking forskolin-induced, Cl−-mediated short-circuit currents in human ADPKD cells, and it significantly inhibited both cAMP- and epidermal growth factor-induced proliferation of ADPKD cells. Western blot analysis of H2-GMZ-treated ADPKD cells showed decreased phosphorylated ERK and decreased hyperphosphorylated retinoblastoma levels. H2-GMZ treatment also decreased ErbB2, Akt, and cyclin-dependent kinase 4, consistent with inhibition of heat shock protein 90, and it decreased levels of the cystic fibrosis transmembrane conductance regulator Cl− channel protein. H2-GMZ-treated ADPKD cultures contained a higher proportion of smaller cells with fewer and smaller lamellipodia and decreased cytoplasmic actin staining, and they were unable to accomplish wound closure even at low H2-GMZ concentrations, consistent with an alteration in the actin cytoskeleton and decreased cell motility. Experiments using mouse metanephric organ cultures showed that H2-GMZ inhibited cAMP-stimulated cyst growth and enlargement. In vivo, H2-GMZ was effective in slowing postnatal cyst formation and kidney enlargement in the Pkd1flox/flox: Pkhd1-Cre mouse model. Thus, H2-GMZ treatment decreases Cl− secretion, cell proliferation, cell motility, and cyst growth. These properties, along with its reported low toxicity, suggest that H2-GMZ might be an attractive candidate for treatment of ADPKD. NEW & NOTEWORTHY Autosomal dominant polycystic kidney disease (ADPKD) is a renal neoplastic disorder characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl− secretion. This study shows that the lonidamine derivative H2-GMZ inhibits Cl− secretion, cell proliferation, and cyst growth, suggesting that it might have therapeutic value for the treatment of ADPKD.
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DOI：
10.1016/j.trsl.2014.11.003
发表时间：
2015-04
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
LaRiviere WB;Irazabal MV;Torres VE
通讯作者：
Torres VE
DOI：
10.1073/pnas.84.23.8394
发表时间：
1987-12-01
影响因子：
11.1
作者：
COWLEY, BD;SMARDO, FL;CALVET, JP
通讯作者：
CALVET, JP
影响因子：
168.9
作者：
Caroli, Anna;Perico, Norberto;Ruggenenti, Piero
通讯作者：
Ruggenenti, Piero
影响因子：
19.6
作者：
Davidow, CJ;Maser, RL;Grantham, JJ
通讯作者：
Grantham, JJ
影响因子：
81.5
作者：
Bergmann, Carsten;Guay-Woodford, Lisa M.;Torres, Vicente E.
通讯作者：
Torres, Vicente E.