Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome.
Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome.
复制标题
循环血管生成素样4将蛋白尿与肾病综合征中的高甘油三酸血症联系起来。
作者：
肾病综合征中蛋白尿和高脂血症之间的分子联系尚不清楚。我们在本研究中表明，血浆血管生成素样4（Angptl 4）通过两个负反馈回路将蛋白尿与高胆固醇血症联系起来。在模拟人类微小病变疾病的大鼠模型中的先前研究中，我们观察到足细胞局部分泌低唾液酸化的Angptl 4（该蛋白的前蛋白尿形式）。但在该研究中，我们也注意到在其他肾小球疾病中的高血清Angptl 4水平（基于中性等电点推测为正常唾液酸化的）。当蛋白尿达到肾病范围时，响应于游离脂肪酸（FFA）与白蛋白的血浆比率升高，由肾外器官分泌循环Angptl 4。在系统反馈回路中，这些Angptl 4循环池通过与肾小球内皮αvβ5整联蛋白相互作用减少蛋白尿。在动物模型中阻断Angptl 4-β5整联蛋白相互作用或Angptl 4或β5整联蛋白的整体敲除延迟从峰值蛋白尿的恢复。但同时，在局部反馈回路中，升高的Angptl 4肾外池通过抑制脂蛋白脂肪酶（LPL）介导的血浆甘油三酯水解为FFA而降低骨骼肌、心脏和脂肪组织中的组织FFA摄取，随后导致高甘油三酯血症。将在关键LPL相互作用位点修饰的重组人ANGPTL 4注射到肾病布法罗Mna和Zucker糖尿病肥胖大鼠中，通过系统环路减少蛋白尿，但通过绕过局部环路，而不增加血浆甘油三酯水平。这些数据显示，响应于肾病范围蛋白尿的循环Angptl 4的增加降低了这种病理的程度，但以诱导高甘油三酯血症为代价，同时还提示了治疗这些相关病理的可能疗法。
The molecular link between proteinuria and hyperlipidemia in nephrotic syndrome is not known. We show in the present study that plasma angiopoietin-like 4 (Angptl4) links proteinuria with hypertriglyceridemia through two negative feedback loops. In previous studies in a rat model that mimics human minimal change disease, we observed localized secretion by podocytes of hyposialylated Angptl4, a pro-proteinuric form of the protein. But in this study we noted high serum levels of Angptl4 (presumably normosialylated based on a neutral isoelectric point) in other glomerular diseases as well. Circulating Angptl4 was secreted by extrarenal organs in response to an elevated plasma ratio of free fatty acids (FFAs) to albumin when proteinuria reached nephrotic range. In a systemic feedback loop, these circulating pools of Angptl4 reduced proteinuria by interacting with glomerular endothelial αvβ5 integrin. Blocking the Angptl4–β5 integrin interaction or global knockout of Angptl4 or β5 integrin delayed recovery from peak proteinuria in animal models. But at the same time, in a local feedback loop, the elevated extrarenal pools of Angptl4 reduced tissue FFA uptake in skeletal muscle, heart and adipose tissue, subsequently resulting in hypertriglyceridemia, by inhibiting lipoprotein lipase (LPL)-mediated hydrolysis of plasma triglycerides to FFAs. Injecting recombinant human ANGPTL4 modified at a key LPL interacting site into nephrotic Buffalo Mna and Zucker Diabetic Fatty rats reduced proteinuria through the systemic loop but, by bypassing the local loop, without increasing plasma triglyceride levels. These data show that increases in circulating Angptl4 in response to nephrotic-range proteinuria reduces the degree of this pathology, but at the cost of inducing hypertriglyceridemia, while also suggesting a possible therapy to treat these linked pathologies.
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DOI：
10.1111/cts.12003
发表时间：
2013-02
期刊：
Clinical and translational science
影响因子：
--
作者：
Ferris M;Norwood V;Radeva M;Gassman JJ;Al-Uzri A;Askenazi D;Matoo T;Pinsk M;Sharma A;Smoyer W;Stults J;Vyas S;Weiss R;Gipson D;Kaskel F;Friedman A;Moxey-Mims M;Trachtman H
通讯作者：
Trachtman H
影响因子：
19.6
作者：
GHIGGERI, GM;GINEVRI, F;GUSMANO, R
通讯作者：
GUSMANO, R
DOI：
10.1073/pnas.0604026103
发表时间：
2006-11-14
影响因子：
11.1
作者：
Sukonina, Valentina;Lookene, Aivar;Olivecrona, Gunilla
通讯作者：
Olivecrona, Gunilla
影响因子：
19.6
作者：
Chugh, S;Yuan, HP;Salant, DJ
通讯作者：
Salant, DJ
影响因子：
15.9
作者：
Le Berre, L;Godfrin, Y;Dantal, J
通讯作者：
Dantal, J