Mineralocorticoid receptor antagonism in diabetes reduces albuminuria by preserving the glomerular endothelial glycocalyx.
Mineralocorticoid receptor antagonism in diabetes reduces albuminuria by preserving the glomerular endothelial glycocalyx.
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DOI：
10.1172/jci.insight.154164
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发表时间：
2023-03-08
期刊：
影响因子：
8
通讯作者：
Butler, Matthew J.
中科院分区：
文献类型：
--
作者：
Crompton, Michael;Ferguson, Joanne K.;Ramnath, Raina D.;Onions, Karen L.;Ogier, Anna S.;Gamez, Monica;Down, Colin J.;Skinner, Laura;Wong, Kitty H.;Dixon, Lauren K.;Sutak, Judit;Harper, Steven J.;Pontrelli, Paola;Gesualdo, Loreto;Heerspink, Hiddo L.;Toto, Robert D.;Welsh, Gavin I.;Foster, Rebecca R.;Satchell, Simon C.;Butler, Matthew J.
肾小球内皮糖萼（GEnGlx）形成肾小球滤过屏障的第一部分。以前，我们发现盐皮质激素受体（MR）激活引起GEnGlx损伤和蛋白尿。在这项研究中，我们调查了MR拮抗剂是否可以限制糖尿病患者的蛋白尿，并研究了作用部位。链脲佐菌素诱导的糖尿病Wistar大鼠出现蛋白尿、肾小球白蛋白渗透性（Ps'alb）增加和肾小球基质金属蛋白酶（MMP）活性增加，伴随相应的GEnGlx损失。MR拮抗作用阻止了蛋白尿的进展，恢复了Ps'alb，保留了GEnGlx，并降低了MMP活性。GEnGlx的酶促降解否定了MR拮抗作用的益处，证实了它们对GEnGlx完整性的依赖性。在体外将人肾小球内皮细胞（GEnC）暴露于糖尿病条件下可增加MMPs并引起糖萼损伤。这些作用的改善证实了MR拮抗作用对GEnC的直接作用。为了证实与人类疾病的相关性，我们使用了一种潜在的新型共聚焦成像方法来显示糖尿病肾病（DN）患者肾活检标本中GEnGlx的丢失。此外，与安慰剂和基线水平相比，随机接受MR拮抗剂治疗的DN患者的尿MMP 2活性和白蛋白尿减少。综上所述，我们的工作表明，MR拮抗剂降低MMP活性，从而保护GEnGlx，导致糖尿病患者肾小球通透性降低和蛋白尿。
The glomerular endothelial glycocalyx (GEnGlx) forms the first part of the glomerular filtration barrier. Previously, we showed that mineralocorticoid receptor (MR) activation caused GEnGlx damage and albuminuria. In this study, we investigated whether MR antagonism could limit albuminuria in diabetes and studied the site of action. Streptozotocin-induced diabetic Wistar rats developed albuminuria, increased glomerular albumin permeability (Ps’alb), and increased glomerular matrix metalloproteinase (MMP) activity with corresponding GEnGlx loss. MR antagonism prevented albuminuria progression, restored Ps’alb, preserved GEnGlx, and reduced MMP activity. Enzymatic degradation of the GEnGlx negated the benefits of MR antagonism, confirming their dependence on GEnGlx integrity. Exposing human glomerular endothelial cells (GEnC) to diabetic conditions in vitro increased MMPs and caused glycocalyx damage. Amelioration of these effects confirmed a direct effect of MR antagonism on GEnC. To confirm relevance to human disease, we used a potentially novel confocal imaging method to show loss of GEnGlx in renal biopsy specimens from patients with diabetic nephropathy (DN). In addition, patients with DN randomized to receive an MR antagonist had reduced urinary MMP2 activity and albuminuria compared with placebo and baseline levels. Taken together, our work suggests that MR antagonists reduce MMP activity and thereby preserve GEnGlx, resulting in reduced glomerular permeability and albuminuria in diabetes.
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影响因子：
2.6
作者：
Ferreira JP;Santos M;Oliveira JC;Marques I;Bettencourt P;Carvalho H
通讯作者：
Carvalho H
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。
影响因子：
19.6
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
通讯作者：
Satchell SC
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：
13
作者：
Ferreira, Joao Pedro;Verdonschot, Job;Zannad, Faiez
通讯作者：
Zannad, Faiez
DOI：
10.1115/1.3138276
发表时间：
1981-01-01
影响因子：
1.7
作者：
DEWEY, CF;BUSSOLARI, SR;DAVIES, PF
通讯作者：
DAVIES, PF