Gene expression profiles of glomerular endothelial cells support their role in the glomerulopathy of diabetic mice

Jia Fu, Chengguo Wei, Weijia Zhang, Detlef Schlondorff, Jinshan Wu, Minchao Cai, Wu He, Margaret H. Baron, Peter Y. Chuang, Zhihong Liu, John Cijiang He, Kyung Lee

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Endothelial dysfunction promotes the pathogenesis of diabetic nephropathy (DN), which is considered to be an early event in disease progression. However, the molecular changes associated with glomerular endothelial cell (GEC) injury in early DN are not well defined. Most gene expression studies have relied on the indirect assessment of GEC injury from isolated glomeruli or renal cortices. Here, we present transcriptomic analysis of isolated GECs, using streptozotocin-induced diabetic wildtype (STZ-WT) and diabetic eNOS-null (STZ-eNOS−/−) mice as models of mild and advanced DN, respectively. GECs of both models in comparison to their respective nondiabetic controls showed significant alterations in the regulation of apoptosis, oxidative stress, and proliferation. The extent of these changes was greater in STZ-eNOS−/− than in STZ-WT GECs. Additionally, genes in STZ-eNOS−/− GECs indicated further dysregulation in angiogenesis and epigenetic regulation. Moreover, a biphasic change in the number of GECs, characterized by an initial increase and subsequent decrease over time, was observed only in STZ-eNOS−/− mice. This is consistent with an early compensatory angiogenic process followed by increased apoptosis, leading to an overall decrease in GEC survival in DN progression. From the genes altered in angiogenesis in STZ-eNOS−/− GECs, we identified potential candidate genes, Lrg1 and Gpr56, whose function may augment diabetes-induced angiogenesis. Thus, our results support a role for GEC in DN by providing direct evidence for alterations of GEC gene expression and molecular pathways. Candidate genes of specific pathways, such as Lrg1 and Gpr56, can be further explored for potential therapeutic targeting to mitigate the initiation and progression of DN.

Original languageEnglish
Pages (from-to)326-345
Number of pages20
JournalKidney International
Volume94
Issue number2
DOIs
StatePublished - Aug 2018

Keywords

  • diabetic nephropathy
  • endothelial nitric oxide synthase
  • glomerular endothelial cells
  • transcriptional profiling

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