Papadopoulos Theofilos, Casemayou Audrey, Neau Eric, Breuil Benjamin, Caubet Cécile, Calise Denis, Thornhill Barbara A, Bachvarova Magdalena, Belliere Julie, Chevalier Robert L, Moulos Panagiotis, Bachvarov Dimcho, Buffin-Meyer Benedicte, Decramer Stéphane, Auriol Françoise Conte, Bascands Jean-Loup, Schanstra Joost P, Klein Julie
Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Metabolic and Cardiovascular Diseases-I2MC, 1 avenue Jean Poulhès, B.P. 84225, 31432, Toulouse Cedex 4, France.
Université Toulouse III Paul-Sabatier, Toulouse, France.
BMC Syst Biol. 2017 Mar 1;11(1):31. doi: 10.1186/s12918-017-0411-7.
Although renal fibrosis and inflammation have shown to be involved in the pathophysiology of obstructive nephropathies, molecular mechanisms underlying evolution of these processes remain undetermined. In an attempt towards improved understanding of obstructive nephropathy and improved translatability of the results to clinical practice we have developed a systems biology approach combining omics data of both human and mouse obstructive nephropathy.
We have studied in parallel the urinary miRNome of infants with ureteropelvic junction obstruction and the kidney tissue miRNome and transcriptome of the corresponding neonatal partial unilateral ureteral obstruction (UUO) mouse model. Several hundreds of miRNAs and mRNAs displayed changed abundance during disease. Combination of miRNAs in both species and associated mRNAs let to the prioritization of five miRNAs and 35 mRNAs associated to disease. In vitro and in vivo validation identified consistent dysregulation of let-7a-5p and miR-29-3p and new potential targets, E3 ubiquitin-protein ligase (DTX4) and neuron navigator 1 (NAV1), potentially involved in fibrotic processes, in obstructive nephropathy in both human and mice that would not be identified otherwise.
Our study is the first to correlate a mouse model of neonatal partial UUO with human UPJ obstruction in a comprehensive systems biology analysis. Our data revealed let-7a and miR-29b as molecules potentially involved in the development of fibrosis in UPJ obstruction via the control of DTX4 in both man and mice that would not be identified otherwise.
尽管肾纤维化和炎症已被证明参与梗阻性肾病的病理生理过程，但这些过程演变的分子机制仍未明确。为了更好地理解梗阻性肾病并提高研究结果向临床实践的转化能力，我们开发了一种系统生物学方法，将人类和小鼠梗阻性肾病的组学数据相结合。
我们同时研究了输尿管肾盂连接部梗阻婴儿的尿液微小RNA组以及相应的新生儿部分单侧输尿管梗阻（UUO）小鼠模型的肾组织微小RNA组和转录组。数百种微小RNA和信使核糖核酸在疾病过程中丰度发生变化。两个物种中微小RNA与相关信使核糖核酸的组合，确定了与疾病相关的5种微小RNA和35种信使核糖核酸的优先级。体外和体内验证确定了人类和小鼠梗阻性肾病中let-7a-5p和miR-29-3p持续失调以及新的潜在靶点——E3泛素蛋白连接酶（DTX4）和神经导航蛋白1（NAV1），这些靶点可能参与纤维化过程，否则无法识别。
我们的研究首次在全面的系统生物学分析中将新生儿部分UUO小鼠模型与人类输尿管肾盂连接部梗阻相关联。我们的数据揭示，let-7a和miR-29b可能通过控制人类和小鼠中的DTX4参与输尿管肾盂连接部梗阻纤维化的发展，否则无法识别。
