Systems approach identifies HIPK2 as a critical regulator of kidney tubulointerstitial fibrosis

We used an integrated computational/experimental systems biology approach to identify upstream protein kinases that regulate gene expression changes in kidneys of HIV-1 transgenic mice (Tg26), which have significant tubulo-interstitial fibrosis (TIF) and glomerulosclerosis (GS). We identified the homeo-domain interacting protein kinase 2 (HIPK2) as a key regulator of TIF and GS. HIPK2 was upregulated in kidneys of Tg26 and patients with various kidney diseases. HIV infection increased the protein level of HIPK2 by promoting oxidative stress, which inhibited Siah1-mediated proteasomal degradation of HIPK2. The data contain two sets: kidney corticies from WT and Tg26 mice and HEK293 transfected with HIPK2, HIPK2-DN and wild type. Gene expression comparison between kidney cortecies of Tg26 HIV mouse model and wild type. Gene expression comparison between 293 HEK cells with HIPK-DN, HIPK-KO and normal.本研究采用整合计算与实验的系统生物学策略，筛选调控HIV-1转基因小鼠（Tg26）肾脏基因表达变化的上游蛋白激酶。该模型小鼠表现出显著的肾小管间质纤维化（tubulo-interstitial fibrosis, TIF）与肾小球硬化（glomerulosclerosis, GS）。本研究鉴定出同源结构域相互作用蛋白激酶2（homeo-domain interacting protein kinase 2, HIPK2）是调控TIF与GS的关键调控因子。HIPK2在Tg26小鼠肾脏及多种肾脏疾病患者的肾脏组织中呈表达上调状态。HIV感染可通过促进氧化应激，抑制Siah1介导的HIPK2蛋白酶体降解，从而提升其蛋白水平。本数据集包含两组样本：野生型（wild type, WT）与Tg26小鼠的肾脏皮质样本，以及转染了HIPK2、显性负效突变型HIPK2（HIPK2-DN）与野生型的HEK293细胞样本。数据集涵盖两类基因表达比较分析：一是Tg26 HIV小鼠模型与野生型小鼠的肾脏皮质基因表达差异分析；二是转染HIPK2-DN、HIPK2-KO与正常HEK293细胞的基因表达差异分析。