Adiponectin accumulation in the retinal vascular endothelium and its possible role in preventing early diabetic microvascular damage

Shunbun Kita,Kohji Nishida,Shiro Fukuda,Barbara Ranscht,Norikazu Maeda,Taka-Aki Sakaue,Hitoshi Nishizawa,Yoko Fukushima,Yuya Fujishima,Iichiro Shimomura,Yuri Tsugawa-Shimizu

doi:10.1038/s41598-022-08041-2

Abstract

Adiponectin (APN), a protein abundantly secreted from adipocytes, has been reported to possess beneficial effects on cardiovascular diseases in association with its accumulation on target organs and cells by binding to T-cadherin. However, little is known about the role of APN in the development of diabetic microvascular complications, such as diabetic retinopathy (DR). Here we investigated the impact of APN on the progression of early retinal vascular damage using a streptozotocin (STZ)-induced diabetic mouse model. Our immunofluorescence results clearly showed T-cadherin-dependent localization of APN in the vascular endothelium of retinal arterioles, which was progressively decreased during the course of diabetes. Such reduction of retinal APN accompanied the early features of DR, represented by increased vascular permeability, and was prevented by glucose-lowering therapy with dapagliflozin, a selective sodium-glucose co-transporter 2 inhibitor. In addition, APN deficiency resulted in severe vascular permeability under relatively short-term hyperglycemia, together with a significant increase in vascular cellular adhesion molecule-1 (VCAM-1) and a reduction in claudin-5 in the retinal endothelium. The present study demonstrated a possible protective role of APN against the development of DR.

Highlights

Adiponectin (APN), a protein abundantly secreted from adipocytes, has been reported to possess beneficial effects on cardiovascular diseases in association with its accumulation on target organs and cells by binding to T-cadherin
Consistent with immunofluorescence results, both T-cadherin and APN proteins were detectable in whole retinal lysates of WT mice, whereas APN was barely detectable in T-cadherin knockout (Tcad-KO) mice
(2) The amount of APN protein in the retinal vascular endothelium was significantly reduced in STZ-induced diabetic mice, accompanied by increased vascular permeability and reduced claudin-5 expression

Summary

Introduction

Adiponectin (APN), a protein abundantly secreted from adipocytes, has been reported to possess beneficial effects on cardiovascular diseases in association with its accumulation on target organs and cells by binding to T-cadherin. Our immunofluorescence results clearly showed T-cadherin-dependent localization of APN in the vascular endothelium of retinal arterioles, which was progressively decreased during the course of diabetes. Such reduction of retinal APN accompanied the early features of DR, represented by increased vascular permeability, and was prevented by glucoselowering therapy with dapagliflozin, a selective sodium-glucose co-transporter 2 inhibitor. In an STZ-induced diabetic model, genetic loss of APN resulted in accelerated induction of early pathological features of DR, represented by increased vascular permeability, indicating the potential action of APN against DR progression

Methods

Results

Conclusion