Overexpression of Circulating Soluble Nogo-B Improves Diabetic Kidney Disease by Protecting the Vasculature.

Abstract

Damage to the vasculature is the primary mechanism driving chronic diabetic microvascular complications such as diabetic nephropathy, which manifests as albuminuria. Therefore, treatments that protect the diabetic vasculature have significant therapeutic potential. Soluble neurite outgrowth inhibitor-B (sNogo-B) is a circulating N-terminus isoform of full-length Nogo-B, which plays a key role in vascular remodeling following injury. However, there is currently no information on the role of sNogo-B in the context of diabetic nephropathy. We demonstrate that overexpression of sNogo-B in the circulation ameliorates diabetic kidney disease by reducing albuminuria, hyperfiltration, and abnormal angiogenesis and protecting glomerular capillary structure. Systemic sNogo-B overexpression in diabetic mice also associates with dampening vascular endothelial growth factor-A signaling and reducing endothelial nitric oxide synthase, AKT, and GSK3β phosphorylation. Furthermore, sNogo-B prevented the impairment of tube formation, which occurred when human endothelial cells were exposed to sera from patients with diabetic kidney disease. Collectively, these studies provide the first evidence that sNogo-B protects the vasculature in diabetes and may represent a novel therapeutic target for diabetic vascular complications.

• Authors: Ivan Hernandez-Diaz, Jiaqi Pan, Carlo Alberto Ricciardi, Xiaoyan Bai, Jianting Ke, Kathryn E White, Maria Flaquer, Georgia E Fouli, Fulye Argunhan, Anthea E Hayward, Fan Fan Hou, Giovanni E Mann, Robert Q Miao, David A Long, Luigi Gnudi
• Journal: Diabetes (Diabetes) Vol. 68 Issue 9 Pg. 1841-1852 (09 2019) ISSN: 1939-327X [Electronic] United States
• PMID: 31217174 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by the American Diabetes Association.

Chemical References

• ANGPT1 protein, human
• Angiopoietin-1
• Angiopoietin-2
• Nogo Proteins
• Vascular Endothelial Growth Factor A
• Nitric Oxide Synthase Type III
• Kdr protein, mouse
• Vascular Endothelial Growth Factor Receptor-2
• Proto-Oncogene Proteins c-akt

Topics

• Angiopoietin-1 (metabolism)
• Angiopoietin-2 (metabolism)
• Animals
• Capillaries (metabolism)
• Diabetes Mellitus, Experimental (blood, genetics, metabolism)
• Diabetic Nephropathies (blood, genetics, metabolism)
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• Kidney Glomerulus (blood supply, metabolism)
• Mice
• Neovascularization, Pathologic (genetics, metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Nogo Proteins (blood, genetics, metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)