MicroRNA-21 regulates peroxisome proliferator-activated receptor alpha, a molecular mechanism of cardiac pathology in Cardiorenal Syndrome Type 4.
MicroRNA-21 regulates peroxisome proliferator-activated receptor alpha, a molecular mechanism of cardiac pathology in Cardiorenal Syndrome Type 4.
复制标题
MicroRNA-21调节过氧化物酶体增殖物激活的受体α，这是心脏综合征4型心脏病理学的分子机制。
DOI：
10.1016/j.kint.2017.05.014
复制
发表时间：
2018-03
影响因子：
19.6
通讯作者：
Kriegel AJ
中科院分区：
文献类型：
--
作者：
Chuppa S;Liang M;Liu P;Liu Y;Casati MC;Cowley AW;Patullo L;Kriegel AJ
心血管事件是慢性肾脏病（CKD）患者死亡的主要原因，尽管其病理机制尚不清楚。在此，我们纵向描述了5/6肾切除大鼠CKD模型的左心室病理学特征，并鉴定了新的分子介质。左心室mRNA和microRNA（miRNA）的下一代测序是在疾病进展的生理学不同点进行的，鉴定了许多免疫、脂质代谢和炎症途径中的基因以及几种miRNA的改变。miRNA miR-21- 5 p在我们的数据集中增加，并且据报道调节许多已鉴定的途径。抑制miR-21- 5 p可保护5/6肾切除大鼠免于发生左心室肥大并改善左心室功能。下一代mRNA测序显示，miR-21- 5 p抑制改变了左心室过氧化物酶体增殖物激活受体α（PPARα）调节途径中的基因表达。PPARα是miR-21- 5 p靶点，是心脏中的主要PPAR亚型，重要参与调节脂肪酸代谢。对5/6肾切除大鼠给予低剂量的PPARα激动剂（氯贝丁酯）可改善心功能并防止左心室扩张。因此，左心室分子变化的综合表征突出了先前在CKD模型中未探索的多种信号传导途径的参与，并将PPARα确定为CKD相关心功能不全的潜在治疗靶点。
Cardiovascular events are the leading cause of death in patients with chronic kidney disease (CKD), although the pathological mechanisms are poorly understood. Here we longitudinally characterized left ventricle pathology in a 5/6 nephrectomy rat model of CKD and identify novel molecular mediators. Next-generation sequencing of left ventricle mRNA and microRNA (miRNA) was performed at physiologically distinct points in disease progression, identifying alterations in genes in numerous immune, lipid metabolism, and inflammatory pathways, as well as several miRNAs. MiRNA miR-21-5p was increased in our dataset and has been reported to regulate many identified pathways. Suppression of miR-21-5p protected rats with 5/6 nephrectomy from developing left ventricle hypertrophy and improved left ventricle function. Next-generation mRNA sequencing revealed that miR-21-5p suppression altered gene expression in peroxisome proliferator-activated receptor alpha (PPARα) regulated pathways in the left ventricle. PPARα, a miR-21-5p target, is the primary PPAR isoform in the heart, importantly involved in regulating fatty acid metabolism. Therapeutic delivery of low-dose PPARα agonist (clofibrate) to rats with 5/6 nephrectomy improved cardiac function and prevented left ventricle dilation. Thus, comprehensive characterization of left ventricle molecular changes highlights the involvement of numerous signaling pathways not previously explored in CKD models and identified PPARα as a potential therapeutic target for CKD-related cardiac dysfunction.
登录
查看更多内容
影响因子：
4.6
作者：
Colombo, Paolo C.;Ganda, Anjali;Lin, Jeffrey;Onat, Duygu;Harxhi, Ante;Iyasere, Julia E.;Uriel, Nir;Cotter, Gad
通讯作者：
Cotter, Gad
DOI：
10.1161/hypertensionaha.114.04179
发表时间：
2015-02
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Geurts AM;Mattson DL;Liu P;Cabacungan E;Skelton MM;Kurth TM;Yang C;Endres BT;Klotz J;Liang M;Cowley AW Jr
通讯作者：
Cowley AW Jr
影响因子：
15.9
作者：
Gomez, Ivan G.;MacKenna, Deidre A.;Duffield, Jeremy S.
通讯作者：
Duffield, Jeremy S.
影响因子：
3.7
作者：
Glowacki F;Savary G;Gnemmi V;Buob D;Van der Hauwaert C;Lo-Guidice JM;Bouyé S;Hazzan M;Pottier N;Perrais M;Aubert S;Cauffiez C
通讯作者：
Cauffiez C
影响因子：
4.8
作者：
Delerive, P;De Bosscher, K;Staels, B
通讯作者：
Staels, B