Diabetes-induced peroxynitrite impairs the balance of pro-nerve growth factor and nerve growth factor, and causes neurovascular injury

Abstract

Aims/hypothesis Diabetic retinopathy, the leading cause of blindness in working-age Americans, is characterised by reduced neurotrophic support and increased proinflammatory cytokines, resulting in neurotoxicity and vascular permeability. We sought to elucidate how oxidative stress impairs homeostasis of nerve growth factor (NGF) and its precursor, proform of NGF (proNGF), to cause neurovascular dysfunction in the eye of diabetic patients. Methods Levels of NGF and proNGF were examined in samples from human patients, from retinal Müller glial cell line culture cells and from streptozotocin-induced diabetic animals treated with and without atorvastatin (10 mg/kg daily, per os) or 5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrinato iron (III) chloride (FeTPPs) (15 mg/kg daily, i.p.) for 4 weeks. Neuronal death and vascular permeability were assessed by TUNEL and extravasation of BSA-fluorescein. Results Diabetes-induced peroxynitrite formation impaired production and activity of matrix metalloproteinase-7 (MMP-7), which cleaves proNGF extracellularly, leading to accumulation of proNGF and reducing NGF in samples from diabetic retinopathy patients and experimental models. Treatment of diabetic animals with atorvastatin exerted similar protective effects that blocked peroxynitrite using FeTPPs, restoring activity of MMP-7 and hence the balance between proNGF and NGF. These effects were associated with preservation of blood-retinal barrier integrity, preventing neuronal cell death and blocking activation of RhoA and p38 mitogen-activated protein kinase (p38MAPK) in experimental and human samples. Conclusions/interpretation Oxidative stress plays an unrecognised role in causing accumulation of proNGF, which can activate a common pathway, RhoA/p38MAPK, to mediate neurovascular injury. Oral statin therapy shows promise for treatment of diabetic retinopathy.

Epicatechin blocks pro-nerve growth factor (proNGF)-mediated retinal neurodegeneration via inhibition of p75 neurotrophin receptor proNGF expression in a rat model of diabetes

“…2a, diabetes induced glial activation as indicated in the filaments of Müller cells by prominent GFAP immunoreactivity extending from the nerve fibre layer and inner plexiform layer into the outer nuclear layer of retina, as compared with controls. Recent studies have identified Müller cells as a major site of proNGF expression in the retina [10,25]. Consistent with this, diabetic retinas showed prominent immunolocalisation of proNGF in Müller cells and inner retinal layers, as indicated by prominent colocalisation of proNGF and GFAP, a marker of Muller activation (Fig.…”

“…We and others have demonstrated increases in expression of nerve growth factor (NGF) in experimental models of diabetes and in clinical diabetes [7][8][9]. Recent findings by our group showed that diabetes-induced peroxynitrite formation impairs cleavage and maturation of NGF, leading to accumulation of its precursor 'proNGF' at the expense of the mature NGF levels, both in experimental models and in clinical diabetes [10]. Accumulation of proNGF after injury has been detected in several neurodegenerative diseases, such as Alzheimer's, [11,12].…”

“…Our previous studies had shown that excessive peroxynitrite formation, as indicated by increases in nitrotyrosine formation, positively correlated with accelerated vascular cell death, blood-retina barrier breakdown and neuronal cell death in models of diabetes, and with ischaemic retinopathy and retinal neurotoxicity [6,7,10,[17][18][19][20][21][22]. Of particular note, our recent study demonstrated a specific role of peroxynitrite in impairing the survival receptor TrkA via tyrosine nitration and upregulation of the death receptor p75 NTR , leading to neuronal death in experimental models and in clinical diabetes [7].…”

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

“…827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 Elevated levels of peroxynitrites have been recently associated to an increased RhoA activity, largely responsible for vascular dysfunction in experimental diabetes [231]. On the same line, diabetesinduced endothelial aortic dysfunction is improved in ROCK knockout mice [232].…”

Neuroinflammation and Neurodegenerative Disorders of the Retina

“…The levels of brain-derived neurotrophic factor (BDNF) [7] and nerve growth factor (NGF) [30] are both decreased in the diabetic retina. NGF is produced from pro-NGF by the proteolytic activity of matrix metalloproteinase (MMP)-7.…”