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

TY - JOUR

T1 - Overexpression of Circulating Soluble Nogo-B Improves Diabetic Kidney Disease by Protecting the Vasculature

AU - Hernandez-Diaz, Ivan

AU - Pan, Jiaqi

AU - Ricciardi, Carlo Alberto

AU - Bai, Xiaoyan

AU - Ke, Jianting

AU - White, Kathryn E

AU - Flaquer, Maria

AU - Fouli, Georgia E

AU - Argunhan, Fulye

AU - Hayward, Anthea E

AU - Hou, Fan Fan

AU - Mann, Giovanni E

AU - Miao, Robert Q

AU - Long, David A

AU - Gnudi, Luigi

N1 - © 2019 by the American Diabetes Association.

PY - 2019/8/20

Y1 - 2019/8/20

N2 - 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 remodelling 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, abnormal angiogenesis and protecting glomerular capillary structure. Systemic sNogo-B overexpression in diabetic mice also associates with dampening VEGF-A signalling and reducing eNOS, 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.

AB - 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 remodelling 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, abnormal angiogenesis and protecting glomerular capillary structure. Systemic sNogo-B overexpression in diabetic mice also associates with dampening VEGF-A signalling and reducing eNOS, 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.

UR - http://www.scopus.com/inward/record.url?scp=85071517347&partnerID=8YFLogxK

U2 - 10.2337/db19-0157

DO - 10.2337/db19-0157

M3 - Article

C2 - 31217174

SN - 0012-1797

VL - 68

SP - 1841

EP - 1852

JO - Diabetes

JF - Diabetes

IS - 9

ER -