Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na⁺/K⁺-ATPase Profibrotic Signaling Pathways.
Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na⁺/K⁺-ATPase Profibrotic Signaling Pathways.
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DOI：
10.3390/ijms19092566
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发表时间：
2018-08-29
影响因子：
5.6
通讯作者：
Tang WHW
中科院分区：
文献类型：
--
作者：
Kennedy DJ;Khalaf FK;Sheehy B;Weber ME;Agatisa-Boyle B;Conic J;Hauser K;Medert CM;Westfall K;Bucur P;Fedorova OV;Bagrov AY;Tang WHW
强心类固醇（CTS）是Na+/K+-ATP酶（NKA）配体，其在体积扩张状态下升高，并且在临床和实验环境中与心脏和肾脏功能障碍相关。在以下研究中，我们检验了CTS端蟾毒精（TCB）在涉及通过NKA α-1进行信号传导的过程中促进肾功能障碍的假设。首先，我们将TCB（0.1 µg/g/d，4周）或溶剂输注到表达野生型（WT）NKA α-1的小鼠以及NKA α-1遗传减少（约40%）的小鼠（NKA α-1+/−）中。连续TCB输注导致WT小鼠中蛋白尿和胱抑素C增加，尽管血压增加相似，但NKA α-1+/−小鼠中蛋白尿和胱抑素C显著减弱（所有p < 0.05）。在一系列体外实验中，用TCB处理HK 2肾近端小管细胞24小时导致胶原蛋白1和3 mRNA的显著剂量依赖性增加（在10 nM时增加2倍，在100 nM时增加5倍，p < 0.05）。在原代人肾系膜细胞中观察到类似的作用。用cSrc重建的SYF成纤维细胞的TCB处理（100 nM）导致胶原蛋白1和3 mRNA增加1.5倍（p < 0.05），以及转化生长因子β 05）和结缔组织生长因子（CTGF，2倍，p <0.05），而这些作用在没有Src激酶的SYF细胞中不存在。在一项针对慢性肾病受试者的患者研究中，与健康志愿者相比，TCB升高。这些研究表明，TCB在肾脏中的促纤维化作用是通过NKA-Src激酶信号传导途径介导的，并且可能与容量超负荷状况相关，例如TCB升高的慢性肾脏疾病。
Cardiotonic steroids (CTS) are Na+/K+-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We test the hypothesis that the CTS telocinobufagin (TCB) promotes renal dysfunction in a process involving signaling through the NKA α-1 in the following studies. First, we infuse TCB (4 weeks at 0.1 µg/g/day) or a vehicle into mice expressing wild-type (WT) NKA α-1, as well as mice with a genetic reduction (~40%) of NKA α-1 (NKA α-1+/−). Continuous TCB infusion results in increased proteinuria and cystatin C in WT mice which are significantly attenuated in NKA α-1+/− mice (all p < 0.05), despite similar increases in blood pressure. In a series of in vitro experiments, 24-h treatment of HK2 renal proximal tubular cells with TCB results in significant dose-dependent increases in both Collagens 1 and 3 mRNA (2-fold increases at 10 nM, 5-fold increases at 100 nM, p < 0.05). Similar effects are seen in primary human renal mesangial cells. TCB treatment (100 nM) of SYF fibroblasts reconstituted with cSrc results in a 1.5-fold increase in Collagens 1 and 3 mRNA (p < 0.05), as well as increases in both Transforming Growth factor beta (TGFb, 1.5 fold, p < 0.05) and Connective Tissue Growth Factor (CTGF, 2 fold, p < 0.05), while these effects are absent in SYF cells without Src kinase. In a patient study of subjects with chronic kidney disease, TCB is elevated compared to healthy volunteers. These studies suggest that the pro-fibrotic effects of TCB in the kidney are mediated though the NKA-Src kinase signaling pathway and may have relevance to volume-overloaded conditions, such as chronic kidney disease where TCB is elevated.
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影响因子：
21.1
作者：
Bagrov AY;Shapiro JI;Fedorova OV
通讯作者：
Fedorova OV
影响因子：
8.8
作者：
Berendes, E;Cullen, P;Walter, M
通讯作者：
Walter, M
影响因子：
19.6
作者：
Kato, N.;Watanabe, Y.;Okada, H.
通讯作者：
Okada, H.
影响因子：
16
作者：
James, PF;Grupp, IL;Lingrel, JB
通讯作者：
Lingrel, JB
影响因子：
3.2
作者：
Haller, Steven T.;Kennedy, David J.;Shidyak, Amjad;Budny, George V.;Malhotra, Deepak;Fedorova, Olga V.;Shapiro, Joseph I.;Bagrov, Alexei Y.
通讯作者：
Bagrov, Alexei Y.