Intravital imaging reveals glomerular capillary distension and endothelial and immune cell activation early in Alport syndrome.
Intravital imaging reveals glomerular capillary distension and endothelial and immune cell activation early in Alport syndrome.
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活体成像显示在奥尔波特综合征早期出现肾小球毛细血管扩张以及内皮细胞和免疫细胞激活。
DOI：
10.1172/jci.insight.152676
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发表时间：
2022-01-11
期刊：
影响因子：
8
通讯作者：
Peti-Peterdi J
中科院分区：
文献类型：
--
作者：
Gyarmati G;Shroff UN;Izuhara A;Hou X;Da Sacco S;Sedrakyan S;Lemley KV;Amann K;Perin L;Peti-Peterdi J
Alport综合征（AS）是由IV型胶原突变引起的遗传性疾病，其导致肾小球基底膜缺陷、肾小球滤过屏障（GFB）损伤和进行性慢性肾病。虽然AS的遗传基础是众所周知的，但疾病发病机制的分子和细胞机制细节一直难以捉摸，阻碍了基于机制的治疗方法的发展。在这里，我们在X连锁AS小鼠模型中对局部肾脏组织微环境进行了活体多光子成像，以直接可视化AS病理学的主要驱动因素。5月龄时发现肾小球毛细血管和动脉瘤严重扩张，伴有大量微血栓、肾小球内皮表面层（糖萼）和免疫细胞归巢增加、GFB白蛋白渗漏、肾小球硬化和间质纤维化，2月龄时表现为中间型。小鼠或患者组织中的肾组织学在很大程度上未能检测到毛细血管畸变。用透明质酸酶或血管紧张素转换酶抑制剂依那普利治疗AS小鼠，减少了肾小球内皮糖萼过多，阻断了免疫细胞归巢和GFB白蛋白渗漏。这项研究确定了肾小球机械力和内皮细胞和免疫细胞活化在AS早期的核心作用，这可以在治疗上靶向减少机械应变和局部组织炎症并改善肾功能。
Alport syndrome (AS) is a genetic disorder caused by mutations in type IV collagen that lead to defective glomerular basement membrane, glomerular filtration barrier (GFB) damage, and progressive chronic kidney disease. While the genetic basis of AS is well known, the molecular and cellular mechanistic details of disease pathogenesis have been elusive, hindering the development of mechanism-based therapies. Here, we performed intravital multiphoton imaging of the local kidney tissue microenvironment in a X-linked AS mouse model to directly visualize the major drivers of AS pathology. Severely distended glomerular capillaries and aneurysms were found accompanied by numerous microthrombi, increased glomerular endothelial surface layer (glycocalyx) and immune cell homing, GFB albumin leakage, glomerulosclerosis, and interstitial fibrosis by 5 months of age, with an intermediate phenotype at 2 months. Renal histology in mouse or patient tissues largely failed to detect capillary aberrations. Treatment of AS mice with hyaluronidase or the ACE inhibitor enalapril reduced the excess glomerular endothelial glycocalyx and blocked immune cell homing and GFB albumin leakage. This study identified central roles of glomerular mechanical forces and endothelial and immune cell activation early in AS, which could be therapeutically targeted to reduce mechanical strain and local tissue inflammation and improve kidney function.
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DOI：
10.1152/ajprenal.00521.2005
发表时间：
2006-08-01
影响因子：
4.2
作者：
Kang, Jung Julie;Toma, Ildiko;Peti-Peterdi, Janos
通讯作者：
Peti-Peterdi, Janos
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：
3.7
作者：
Sun YB;Qu X;Zhang X;Caruana G;Bertram JF;Li J
通讯作者：
Li J
影响因子：
13.6
作者：
Nakano, Daisuke;Kobori, Hiroyuki;Peti-Peterdi, Janos
通讯作者：
Peti-Peterdi, Janos
影响因子：
13.6
作者：
Ichimura, Koichiro;Stan, Radu V.;Sakai, Tatsuo
通讯作者：
Sakai, Tatsuo