Aldosterone induces albuminuria via matrix metalloproteinase-dependent damage of the endothelial glycocalyx.
Aldosterone induces albuminuria via matrix metalloproteinase-dependent damage of the endothelial glycocalyx.
复制标题
醛固酮通过基质金属蛋白酶依赖性糖蛋白糖脂诱导蛋白尿。
DOI：
10.1016/j.kint.2018.08.024
复制
发表时间：
2019-01
影响因子：
19.6
通讯作者：
Satchell SC
中科院分区：
文献类型：
--
作者：
Butler MJ;Ramnath R;Kadoya H;Desposito D;Riquier-Brison A;Ferguson JK;Onions KL;Ogier AS;ElHegni H;Coward RJ;Welsh GI;Foster RR;Peti-Peterdi J;Satchell SC
醛固酮有助于心力衰竭和慢性肾脏疾病的终末器官损伤。矿化皮质激素受体抑制剂限制醛固酮对受体的激活，减缓疾病进展，但副作用，包括高钾血症，限制了它们的临床应用。内皮糖萼（一种管腔生物聚合物层）的损伤与内皮功能障碍和蛋白尿的发病机制有关，但迄今为止还没有人研究过醛固酮是否影响肾小球内皮糖萼。在体外，暴露于0.1 nM醛固酮和145 mMol NaCl下的人肾小球内皮细胞表现出细胞表面糖萼成分（硫酸肝素和syndecan-4）减少，剪切传感中断，与糖萼损伤一致。体内给药0.6 μg/g/d的醛固酮（皮下微型泵）和1% NaCl饮用水使肾小球基质金属蛋白酶2活性升高，syndecan 4表达降低，引起蛋白尿。活体多光子成像证实醛固酮引起肾小球内皮糖盏损伤，增加肾小球对白蛋白的筛分系数。特异性明胶酶抑制剂靶向基质金属蛋白酶2和9，保护糖萼，阻断肾小球筛分系数的升高，预防蛋白尿。这些数据表明，保存肾小球内皮糖萼可能是限制醛固酮病理作用的一种新策略。
Aldosterone contributes to end-organ damage in heart failure and chronic kidney disease. Mineralocorticoid-receptor inhibitors limit activation of the receptor by aldosterone and slow disease progression, but side effects, including hyperkalemia, limit their clinical use. Damage to the endothelial glycocalyx (a luminal biopolymer layer) has been implicated in the pathogenesis of endothelial dysfunction and albuminuria, but to date no one has investigated whether the glomerular endothelial glycocalyx is affected by aldosterone. In vitro, human glomerular endothelial cells exposed to 0.1 nM aldosterone and 145 mMol NaCl exhibited reduced cell surface glycocalyx components (heparan sulfate and syndecan-4) and disrupted shear sensing consistent with damage of the glycocalyx. In vivo, administration of 0.6 μg/g/d of aldosterone (subcutaneous minipump) and 1% NaCl drinking water increased glomerular matrix metalloproteinase 2 activity, reduced syndecan 4 expression, and caused albuminuria. Intravital multiphoton imaging confirmed that aldosterone caused damage of the glomerular endothelial glycocalyx and increased the glomerular sieving coefficient for albumin. Targeting matrix metalloproteinases 2 and 9 with a specific gelatinase inhibitor preserved the glycocalyx, blocked the rise in glomerular sieving coefficient, and prevented albuminuria. Together these data suggest that preservation of the glomerular endothelial glycocalyx may represent a novel strategy for limiting the pathological effects of aldosterone.
登录
查看更多内容
影响因子：
5.8
作者：
McGraw AP;McCurley A;Preston IR;Jaffe IZ
通讯作者：
Jaffe IZ
影响因子：
5.4
作者：
Manon-Jensen, Tina;Multhaupt, Hinke A. B.;Couchman, John R.
通讯作者：
Couchman, John R.
DOI：
10.1161/hypertensionaha.113.01967
发表时间：
2014-03
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Galmiche G;Pizard A;Gueret A;El Moghrabi S;Ouvrard-Pascaud A;Berger S;Challande P;Jaffe IZ;Labat C;Lacolley P;Jaisser F
通讯作者：
Jaisser F
影响因子：
2.3
作者：
Currie G;Taylor AH;Fujita T;Ohtsu H;Lindhardt M;Rossing P;Boesby L;Edwards NC;Ferro CJ;Townend JN;van den Meiracker AH;Saklayen MG;Oveisi S;Jardine AG;Delles C;Preiss DJ;Mark PB
通讯作者：
Mark PB
影响因子：
3.7
作者：
Gilet, Alexandre;Zou, Feng;Ropars, Armelle
通讯作者：
Ropars, Armelle