Dicarbonyl-modified lipoproteins contribute to proteinuric kidney injury.
Dicarbonyl-modified lipoproteins contribute to proteinuric kidney injury.
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DOI：
10.1172/jci.insight.161878
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发表时间：
2022-11-08
期刊：
影响因子：
8
通讯作者：
Kon, Valentina
中科院分区：
文献类型：
--
作者：
Zhong, Jianyong;Yang, Hai -Chun;Shelton, Elaine L.;Matsusaka, Taiji;Clark, Amanda J.;Yermalitsky, Valery;Mashhadi, Zahra;May-Zhang, Linda S.;Linton, MacRae F.;Fogo, Agnes B.;Kirabo, Annet;Davies, Sean S.;Kon, Valentina
脂蛋白被反应性二羰基修饰，包括异丁香苷（IsoLG），产生功能障碍的颗粒。肾脏参与脂蛋白代谢，包括肾小管摄取。然而，近端小管以外的过程尚不清楚，肾损伤对该途径的影响也不清楚。我们发现，与其他蛋白质相比，尿蛋白损伤的患者和动物的尿载脂蛋白AI（apoAI），IsoLG和IsoLG加合物富集的尿apoAI部分。足细胞特异性损伤诱导的蛋白尿小鼠，显示出更多的肾小管吸收的IsoLG-apoAI和增加表达的脂蛋白转运蛋白在近端肾小管细胞相比，未受伤的动物。肾淋巴反映了间质室的组成，并显示蛋白尿动物中apoAI和IsoLG增加，支持肾小管细胞-肾小管-淋巴通路用于肾处理脂蛋白。IsoLG修饰的apoAI不仅是肾损伤的标志物，而且直接损伤肾细胞。与未修饰的apoAI相比，IsoLG-apoAI增加了培养的肾小管上皮细胞（TECs）中的炎性细胞因子，激活了淋巴管内皮细胞（LECs），并引起了肾淋巴管的更大收缩。在体内，通过二羰基清除剂抑制IsoLG可减少白蛋白尿和尿apoAI，并减少TEC和LEC损伤、淋巴管生成和间质纤维化。我们的研究结果表明，据我们所知，IsoLG修饰的apoAI是肾脏疾病的一种新的致病介质和治疗靶点。
Lipoprotein modification by reactive dicarbonyls, including isolevuglandin (IsoLG), produces dysfunctional particles. Kidneys participate in lipoprotein metabolism, including tubular uptake. However, the process beyond the proximal tubule is unclear, as is the effect of kidney injury on this pathway. We found that patients and animals with proteinuric injury have increased urinary apolipoprotein AI (apoAI), IsoLG, and IsoLG adduct enrichment of the urinary apoAI fraction compared with other proteins. Proteinuric mice, induced by podocyte-specific injury, showed more tubular absorption of IsoLG-apoAI and increased expression of lipoprotein transporters in proximal tubular cells compared with uninjured animals. Renal lymph reflects composition of the interstitial compartment and showed increased apoAI and IsoLG in proteinuric animals, supporting a tubular cell-interstitium-lymph pathway for renal handling of lipoproteins. IsoLG-modified apoAI was not only a marker of renal injury but also directly damaged renal cells. IsoLG-apoAI increased inflammatory cytokines in cultured tubular epithelial cells (TECs), activated lymphatic endothelial cells (LECs), and caused greater contractility of renal lymphatic vessels than unmodified apoAI. In vivo, inhibition of IsoLG by a dicarbonyl scavenger reduced both albuminuria and urinary apoAI and decreased TEC and LEC injury, lymphangiogenesis, and interstitial fibrosis. Our results indicate that IsoLG-modified apoAI is, to our knowledge, a novel pathogenic mediator and therapeutic target in kidney disease.
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影响因子：
--
作者：
Ge M;Merscher S;Fornoni A
通讯作者：
Fornoni A
影响因子：
19.6
作者：
Motoyoshi, Yaeko;Matsusaka, Taiji;Saito, Akihiko;Pastan, Ira;Willnow, Thomas E.;Mizutani, Shuki;Ichikawa, Iekuni
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Ichikawa, Iekuni
影响因子：
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Kon V
影响因子：
4.8
作者：
May-Zhang, Linda S.;Yermalitsky, Valery;Davies, Sean S.
通讯作者：
Davies, Sean S.
DOI：
10.1161/atvbaha.115.305777
发表时间：
2015-11-01
影响因子：
8.7
作者：
Bisoendial, Radjesh;Tabet, Fatiha;Rye, Kerry-Anne
通讯作者：
Rye, Kerry-Anne