LRG1 promotes diabetic kidney disease progression by enhancing TGF-b–induced angiogenesis

Quan Hong, Lu Zhang, Jia Fu, Divya A. Verghese, Kinsuk Chauhan, Girish N. Nadkarni, Zhengzhe Li, Wenjun Ju, Matthias Kretzler, Guang Yan Cai, Xiang Mei Chen, Vivette D. D’Agati, Steven G. Coca, Detlef Schlondorff, John C. He, Kyung Lee

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

Background Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich a-2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-b/activin receptor-like kinase 1 (ALK1) signaling. However, LRG1’s role in the kidney, particularly in the setting of DKD, has been unclear. Methods We analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA in situ hybridization. We examined the effects of genetic ablation of Lrg1 on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes. Results LRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes. Conclusions These findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression.

Original languageEnglish
Pages (from-to)546-562
Number of pages17
JournalJournal of the American Society of Nephrology : JASN
Volume30
Issue number4
DOIs
StatePublished - Apr 2019

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