Comprehensive genomic profiling in diabetic nephropathy reveals the predominance of proinflammatory pathways
Comprehensive genomic profiling in diabetic nephropathy reveals the predominance of proinflammatory pathways
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DOI：
10.1152/physiolgenomics.00028.2013
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发表时间：
2013-08-01
影响因子：
4.6
通讯作者：
Dominguez, Jesus H.
中科院分区：
文献类型：
--
作者：
Kelly, K. J.;Liu, Yunlong;Dominguez, Jesus H.
尽管在糖尿病肾病（DN）的治疗方面取得了进展，但目前可用的治疗方法尚未阻止进行性慢性肾病（CKD）的流行。CKD的发病率和终末期肾病患病率的不可避免的增加，需要更有效的方法来预防和治疗进展性CKD。我们在糖尿病肾病大鼠模型中进行了下一代测序，以深入研究DN伴进行性CKD的致病性改变。我们采用肥胖的糖尿病ZS大鼠，这是一种发展糖尿病肾病的模型，其特征在于进行性CKD、炎症和纤维化，这是人类疾病的标志。然后，我们使用RNA-seq来检查肾细胞和浸润性炎症细胞作为病理生理单位的联合作用。进行性CKD的综合系统生物学分析揭示了整合到病态网络中的改变基因的多种相互作用。这些病理性基因组装导致肾脏炎症并促进进行性CKD中的细胞凋亡和细胞周期停滞。此外，在显然是一个主要的治疗挑战中，发现多个和冗余的途径与肾纤维化有关，这是肾功能丧失的主要原因。我们的结论是，系统生物学应用于进展性CKD的DN可用于开发新的治疗策略，旨在恢复受影响的基因网络的关键异常。
Despite advances in the treatment of diabetic nephropathy (DN), currently available therapies have not prevented the epidemic of progressive chronic kidney disease (CKD). The morbidity of CKD, and the inexorable increase in the prevalence of end-stage renal disease, demands more effective approaches to prevent and treat progressive CKD. We undertook next-generation sequencing in a rat model of diabetic nephropathy to study in depth the pathogenic alterations involved in DN with progressive CKD. We employed the obese, diabetic ZS rat, a model that develops diabetic nephropathy, characterized by progressive CKD, inflammation, and fibrosis, the hallmarks of human disease. We then used RNA-seq to examine the combined effects of renal cells and infiltrating inflammatory cells acting as a pathophysiological unit. The comprehensive systems biology analysis of progressive CKD revealed multiple interactions of altered genes that were integrated into morbid networks. These pathological gene assemblies lead to renal inflammation and promote apoptosis and cell cycle arrest in progressive CKD. Moreover, in what is clearly a major therapeutic challenge, multiple and redundant pathways were found to be linked to renal fibrosis, a major cause of kidney loss. We conclude that systems biology applied to progressive CKD in DN can be used to develop novel therapeutic strategies directed to restore critical anomalies in affected gene networks.