Human Alpha-1 Antitrypsin Attenuates ENaC and MARCKS and Lowers Blood Pressure in Hypertensive Diabetic db/db Mice.
Human Alpha-1 Antitrypsin Attenuates ENaC and MARCKS and Lowers Blood Pressure in Hypertensive Diabetic db/db Mice.
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DOI：
10.3390/biom13010066
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发表时间：
2022-12-29
期刊：
影响因子：
5.5
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中科院分区：
文献类型：
--
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高血压可能在糖尿病发作之前或之后发生，并且已知会增加发生糖尿病肾病的风险。α-1抗胰蛋白酶（AAT）是一种多功能蛋白质，对多种疾病具有有益作用，但其在糖尿病肾病中降低血压的作用尚未得到彻底研究。与血压一样，上皮钠通道（ENaC）及其衔接蛋白肉豆蔻酰化富含丙氨酸的C激酶底物（MARCKS）也受昼夜节律的调节。我们的假设是，管理的人AAT（hAAT）降低高血压糖尿病小鼠的血压，通过减弱ENaC的膜表达及其与肌动蛋白细胞骨架的关联。首先，我们显示在非活性和活性周期中，与载体治疗相比，hAAT施用导致糖尿病db/db小鼠的血压降低。蛋白质印迹和免疫组织化学分析显示，与载体相比，用hAAT处理的糖尿病db/db小鼠的肾脏中ENaC和肌动蛋白细胞骨架蛋白MARCKS减少。在非活性和活性周期中，与载体治疗相比，hAAT治疗导致糖尿病db/db小鼠尿液中存在的细胞外囊泡的量升高。与媒介物处理的小鼠相比，在从hAAT处理的高血压糖尿病小鼠释放的尿EV中，多种己糖神经酰胺以及其他脂质类别增加。总之，这些数据表明hAAT治疗可以使糖尿病肾脏中的血压正常化，其机制涉及肾ENaC和MARCKS蛋白表达的减弱以及肾细胞中神经酰胺代谢为己糖基神经酰胺的可能性。
Hypertension may develop before or after the onset of diabetes and it is known to increase the risk of developing diabetic nephropathy. Alpha-1 antitrypsin (AAT) is a multi-functional protein with beneficial effects in various diseases but its role in reducing blood pressure in the diabetic kidney has not been thoroughly studied. Like blood pressure, epithelial sodium channels (ENaC) and its adaptor protein myristoylated alanine-rich C-kinase substrate (MARCKS) are regulated by circadian rhythms. Our hypothesis is that administration of human AAT (hAAT) reduces blood pressure in hypertensive diabetic mice by attenuating membrane expression of ENaC and its association with the actin cytoskeleton. First, we show hAAT administration results in reduced blood pressure in diabetic db/db mice compared to vehicle treatment in both the inactive and active cycles. Western blotting and immunohistochemistry analyses showed a reduction of ENaC and the actin cytoskeleton protein, MARCKS in the kidneys of diabetic db/db mice treated with hAAT compared to vehicle. hAAT treatment resulted in elevated amounts of extracellular vesicles present in the urine of diabetic db/db mice compared to vehicle treatment both in the inactive and active cycles. Multiple hexosylceramides, among other lipid classes increased in urinary EVs released from hAAT treated hypertensive diabetic mice compared to vehicle treated mice. Taken together, these data suggest hAAT treatment could normalize blood pressure in the diabetic kidney in a mechanism involving attenuation of renal ENaC and MARCKS protein expression and possibly ceramide metabolism to hexosylceramide in kidney cells.
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影响因子：
4.2
作者：
Akbar, Mohammad Ahsanul;Cao, Jay J.;Song, Sihong
通讯作者：
Song, Sihong
影响因子：
5.5
作者：
Chacko KM;Nouri MZ;Schramm WC;Malik Z;Liu LP;Denslow ND;Alli AA
通讯作者：
Alli AA
影响因子：
20.1
作者：
DREXLER, H;HIRTH, C;JUST, H
通讯作者：
JUST, H
影响因子：
3.9
作者：
Elshikha, Ahmed S.;Abboud, Georges;Song, Sihong
通讯作者：
Song, Sihong
影响因子：
3.7
作者：
Jella KK;Yu L;Yue Q;Friedman D;Duke BJ;Alli AA
通讯作者：
Alli AA