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Abstract: FR-PO384

LRG1 Promotes DN Progression by Enhancing TGF-β-Induced Angiogenesis

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Hong, Quan, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Zhang, Lu, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Fu, Jia, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States
  • Chen, Xiangmei, Chinese PLA General Hospital, Bei Jing, BEIJING, China
  • Coca, Steven G., Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Schlondorff, Detlef O., Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
Background

Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in pathogenesis of diabetic nephropathy (DN). However, specific molecular pathways contributing to these processes in the early stages of DN injury is not well understood. Our recent transcriptomic profiling of isolated glomerular endothelial cells identified number of pro-angiogenic genes that were upregulated in the diabetic mice, including leucine-rich alpha-2 glycoprotein-1 (LRG1). LRG1, a secreted glycoprotein belonging to a leucine-rich repeat family, was previously shown to promote neovascularization in models of ocular disease by potentiating the TGF-β/ALK1 signaling in endothelial cells. However its role in kidney cells, particularly in the setting of DN, was not known.

Methods

We analyzed the expression pattern of LRG1 in murine and human diabetic kidneys in comparison to normal kidneys by utilizing the RNA-sequencing data of isolated glomeruli and by RNA in situ hybridization. We examined the effects of high glucose conditions on LRG1 cultured murine glomerular endothelial cells (mGECs) in vitro. We then examined the effects of genetic ablation of Lrg1 in DN progression in diabetic mice at 12 weeks and at later time point of 20 weeks post diabetes induction.

Results

We found that LRG1 mRNA expression is significantly increased in glomeruli of mouse and human diabetic kidneys and that its expression localizes predominantly with the glomerular endothelial cells (GECs). High glucose conditions led to the upregulation of LRG1 expression in cultured mGECs, and shRNA-mediated knockdown of Lrg1 led to reduction in endothelial tube formation in vitro. Genetic ablation of Lrg1 in mice markedly attenuated diabetes-induced angiogenesis, albuminuria and glomerulopathy at 12 and 20 weeks of diabetes. These improvements were associated with reduced ALK1-Smad1/5/8 activation and with reduced number of GECs in glomeruli of diabetic mice. Moreover, we found that plasma LRG1 levels were associated with worsened renal outcome in type 2 diabetic patient cohort from BioMe Biobank.

Conclusion

Together, our results identify LRG1 as a potential novel pathogenic mediator of glomerular angiogenesis in diabetic kidneys and a risk factor of DN progression, and suggest that LRG1 may be a promising therapeutic target against the disease progression.

Funding

  • NIDDK Support