Uncoupling of the VEGF-endothelial nitric oxide axis in diabetic nephropathy: an explanation for the paradoxical effects of VEGF in renal disease

Abstract

In many forms of experimental kidney diseases, renal VEGF is low, and administering VEGF can be shown to be protective. A paradox occurs in diabetes, in which renal VEGF levels are high and a deleterious effect of VEGF on kidney disease has been shown. We have hypothesized that endothelial dysfunction induced by hyperglycemia or other factors may underlie the pathogenic mechanisms of a high VEGF state. VEGF normally stimulates endothelial nitric oxide (NO) release and acts in concert with elevated NO levels as a trophic factor for vascular endothelium. The increased NO derived from the endothelial cell acts as an inhibitory factor that prevents excess endothelial cell proliferation, vascular smooth muscle cell proliferation, and macrophage infiltration. In the setting where NO bioavailability is reduced in diabetes, high levels of VEGF lead to excessive endothelial cell proliferation, stimulation of macrophage chemotaxis, and vascular smooth muscle cell activation. Consistent with this hypothesis is our recent observation that diabetes induced in endothelial NO-deficient mice results in clinical and histological features identical to human diabetic nephropathy. The discovery of the key role for impaired endothelial NO bioavailability in the stimulation of VEGF and VEGF-dependent disease may provide key insights into not only the pathogenesis of diabetic nephropathy but also the utility and hazard of administering VEGF as a treatment for kidney disease.

The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy

“…20 Thus, negative regulation of VEGFRs by NO could be a key mechanism to maintain vascular integrity and macrophage migration under VEGF stimulation. 18 Our findings that NO negatively regulated the cell spreading response in macrophages in response to VEGF are also compatible with previous studies that have shown that NO could inhibit actin polymerization in response to VEGF on neutrophils. 36 In summary, VEGF activates macrophage migration by Flt-1.…”

“…We have recently reported that diabetic endothelial nitric oxide synthase (eNOS)-deficient mice develop advanced diabetic nephropathy, characterized by mesangial expansion, basement membrane thickening, mesangiolysis, glomerular microaneurysms and Kimmelstiel-Wilson-like nodules, all of which characterize human diabetic nephropathy. 17 Interestingly, these advanced lesions were accompanied with an increase in renal VEGF expression, suggesting that uncoupling of VEGF with endothelial NO could provoke severe glomerular lesions (reviewed in Nakagawa 18 ). Here, we examined the association of macrophage infiltration with VEGF in glomerular lesions of diabetic eNOS-deficient mice.…”

Targeted Glomerular Angiopoietin-1 Therapy for Early Diabetic Kidney Disease

“…34 Part of this effect is probably due to the attenuation of VEGF-A signaling, which contributes to vascular stability by limiting blood vessel proliferation. In addition, Angpt1 increases eNOS Ser 1177 phosphorylation, resulting in sustained nitric oxide levels, 35 which preserves the integrity of interendothelial junctions in capillaries and inhibits angiogenesis and vascular permeability, 36,37 in physiologic nondiabetic conditions. 38 In our study, we demonstrated that eNOS Ser 1177 phosphorylation was markedly increased in diabetic mice when Angpt1 levels were restored.…”

Associations of functional and biochemical parameters of endothelial dysfunction in postmenopausal women with a different state of carbohydrate metabolism

“…Известно, что VEGF стимулирует высвобождение NO как трофического фак-тора для эндотелия, при этом сам является сильным ми-тогеном для эндотелиоцитов. Эта реакция регулируется по принципу обратной связи [21]: повышенный уровень NO подавляет активность VEGF. Со временем при диа-бете этот процесс нарушается, происходит разобщение оси «NO-VEGF», и несдерживаемый высокий уровень фактора роста эндотелия сосудов приводит к развитию и прогрессированию осложнений [22].…”