title: Comprehensive genomic profiling in diabetic nephropathy reveals the predominance of proinflammatory pathways.
abstract: 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.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Kelly
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.forename: Jizhong
authors.initials: J
authors.lastname: Zhang
authors.forename: Chirayu
authors.initials: C
authors.lastname: Goswami
authors.forename: Hai
authors.initials: H
authors.lastname: Lin
authors.forename: Jesus H
authors.initials: JH
authors.lastname: Dominguez
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003928:Diabetic Nephropathies / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D059014:High-Throughput Nucleotide Sequencing; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D007674:Kidney Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D049490:Systems Biology; D059467:Transcriptome
keywords: diabetic nephropathies; inflammation; renal failure