Cardiac Myocyte-Derived Follistatin-Like 1 Prevents Renal Injury in a Subtotal Nephrectomy Model
Cardiac Myocyte-Derived Follistatin-Like 1 Prevents Renal Injury in a Subtotal Nephrectomy Model
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DOI：
10.1681/asn.2014020210
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发表时间：
2015-03-01
影响因子：
13.6
通讯作者：
Ouchi, Noriyuki
中科院分区：
文献类型：
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作者：
Hayakawa, Satoko;Ohashi, Koji;Ouchi, Noriyuki
心脏病有助于CKD的进展。心脏组织产生许多分泌的蛋白质，也称为心因子，其参与细胞间和组织间的通讯。我们最近报道，卵泡抑素样1（Fstl 1）的功能作为一种心脏因子与心脏保护特性。在此，我们研究心脏Fstl 1在肾大部切除术后肾损伤中的作用。对心脏特异性Fstl 1缺陷（cFstl 1-KO）小鼠和野生型小鼠进行次全（5/6）肾强直。与野生型小鼠相比，cFstl 1-KO小鼠在次全肾消融后表现出尿白蛋白排泄、肾小球神经肥大和肾小管间质纤维化加重。cFstl 1-KO小鼠在残肾中还表现出促炎细胞因子（包括TNF-α和IL-6、NADPH氧化酶组分和纤维化介质）的mRNA水平升高。相反，表达Fstl 1的腺病毒载体（Ad-Fstl 1）的野生型小鼠与次全肾强直的全身管理导致改善白蛋白尿，肾小球肥大，肾小管间质纤维化，伴随着减少表达的促炎介质，NADPH氧化酶成分，和残余肾纤维化标志物。在培养的人肾小球系膜细胞中，用重组FSTL 1治疗减弱了TNF-α刺激的促炎细胞因子的表达。用FSTL 1处理肾小球系膜细胞增强了AMP激活蛋白激酶（AMPK）的磷酸化，抑制AMPK的激活消除了FSTL 1的抗炎作用。这些数据表明，Fstl 1的功能，心肾通讯和Fstl 1生产的肌细胞的缺乏，促进肾小球和肾小管间质损伤的肾脏。
Heart disease contributes to the progression of CKD. Heart tissue produces a number of secreted proteins, also known as cardiokines, which participate in intercellular and intertissue communication. We recently reported that follistatin-like 1 (Fstl1) functions as a cardiokine with cardioprotective properties. Here, we investigated the role of cardiac Fstl1 in renal injury after subtotal nephrectomy. Cardiac-specific Fstl1-deficient (cFstl1-KO) mice and wild-type mice were subjected to subtotal (5/6) nephrectonny. cFstl1-KO mice showed exacerbation of urinary albumin excretion, glonnerular hypertrophy, and tubulointerstitial fibrosis after subtotal renal ablation compared with wild-type mice. cFstl1-KO mice also exhibited increased mRNA levels of proinflammatory cytokines, including TNF-alpha and IL-6, NADPH oxidase components, and fibrotic mediators, in the remnant kidney. Conversely, systemic administration of adenoviral vectors expressing Fstl1 (Ad-Fstl1) to wild-type mice with subtotal nephrectonny led to amelioration of albuminuria, glomerular hypertrophy, and tubulointerstitial fibrosis, accompanied by reduced expression of proinflammatory mediators, NADPH oxidase components, and fibrotic markers in the remnant kidney. In cultured human mesangial cells, treatment with recombinant FSTL1 attenuated TNF-alpha-stimulated expression of proinflammatory cytokines. Treatment of mesangial cells with FSTL1 augmented the phosphorylation of AMP-activated protein kinase (AMPK), and inhibition of AMPK activation abrogated the anti-inflammatory effects of FSTL1. These data suggest that Fstl1 functions in cardiorenal communication and that the lack of Fstl1 production by myocytes promotes glonnerular and tubulointerstitial damage in the kidney.