Role of Nitrosative Stress and Peroxynitrite in the Pathogenesis of Diabetic Complications. Emerging New Therapeutical Strategies

Abstract

Macro-and microvascular disease are the most common causes of morbidity and mortality in patients with diabetes mellitus. Diabetic cardiovascular dysfunction represents a problem of great clinical importance underlying the development of various severe complications including retinopathy, nephropathy, neuropathy and increase the risk of stroke, hypertension and myocardial infarction. Hyperglycemic episodes, which complicate even well-controlled cases of diabetes, are closely associated with increased oxidative and nitrosative stress, which can trigger the development of diabetic complications. Hyperglycemia stimulates the production of advanced glycosylated end products, activates protein kinase C, and enhances the polyol pathway leading to increased superoxide anion formation. Superoxide anion interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, leading to cardiovascular dysfunction. The pathogenetic role of nitrosative stress and peroxynitrite, and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation, is not limited to the diabetes-induced cardiovascular dysfunction, but also contributes to the development and progression of diabetic nephropathy, retinopathy and neuropathy. Accordingly, neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy and prevention of diabetic complications. This review focuses on the role of nitrosative stress and downstream mechanisms including activation of PARP in diabetic complications and on novel emerging therapeutical strategies offered by neutralization of peroxynitrite and inhibition of PARP.

Diabetic Nephropathy Is Associated with Oxidative Stress and Decreased Renal Nitric Oxide Production

“…30 Our findings of increased peroxynitrite in renal cortical homogenates of obese ZSF 1 rats strongly support the conclusion that this rat model of DN is associated with severe oxidative stress. This pathway may account partly for the decreased bioavailability of NO in the kidney.…”

A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocin-diabetic mice

“…Theoretically, nitrosative stress can contribute to diabetic sensory neuropathy via several mechanisms and, in particular, impairment in neurotrophic support and PARP activation Pacher et al, 2005;Szabo et al, 2002a). As indicated above, neurotrophic factors as well as PARP inhibitors prevented thermal hypoalgesia in STZ-diabetic rats (Calcutt et al, 2000Obrosova et al, 2007a).…”

“…Intraepidermal nerve fiber loss; Nitrosative stress; Peroxynitrite decomposition catalyst; Poly(ADPribose) polymerase; Tactile allodynia; Thermal hypoalgesia Evidence for important role of the potent oxidant peroxynitrite, a product of superoxide anion radicals with nitric oxide, in the pathogenesis of diabetes (Olcott et al, 2004;Szabo et al, 2002a;Pacher et al, 2007) and diabetic complications (Nangle et al, 2004;Obrosova et al, 2005b;Pacher et al, 2005;Pacher et al, 2007;Szabo et al, 2002a) is emerging. Accumulation of nitrotyrosine [NT, a footprint of peroxynitrite-and other reactive nitrogen species (RNS)-induced protein nitration] has been documented in vascular endothelium (Pacher et al, 2005;Szabo et al, 2002b), myocardium (Pacher et al, 2005), retina (Cheung et al, 2005;Obrosova et al, 2005c), and kidneys (Drel et al, 2006b) of streptozotocin-diabetic rats and mice as well as cutaneous microvascular endothelium (Szabo et al, 2002b), myocardium (Frustaci et al, 2000), and kidneys (Thuraisingham et al, 2000) of human subjects with diabetes.…”

“…Accumulation of nitrotyrosine [NT, a footprint of peroxynitrite-and other reactive nitrogen species (RNS)-induced protein nitration] has been documented in vascular endothelium (Pacher et al, 2005;Szabo et al, 2002b), myocardium (Pacher et al, 2005), retina (Cheung et al, 2005;Obrosova et al, 2005c), and kidneys (Drel et al, 2006b) of streptozotocin-diabetic rats and mice as well as cutaneous microvascular endothelium (Szabo et al, 2002b), myocardium (Frustaci et al, 2000), and kidneys (Thuraisingham et al, 2000) of human subjects with diabetes. Increased NT immunoreactivity has also been demonstrated in peripheral nervous system i.e., peripheral nerve, spinal cord and dorsal root ganglion (DRG) neurons, of STZ-diabetic rats (Cheng and Zochodne, 2003;Obrosova et al, 2005a) and STZ-diabetic (Ho et al, 2006;Obrosova et al, 2005b), ob/ob (Drel et al, 2006a), and high-fat diet fed mice (Obrosova et al, 2007b), and epineurial vessels of STZ-diabetic, ZDF diabetic fatty, and Zucker fatty rats (Coppey et al, 2001;Obrosova et al, 2005a,b;Oltman et al, 2005).…”

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

“…On the other hand, overproduction of nitric oxide, which is mainly induced by iNOS, has hazardous effects on development. Such overproduction has been shown to exert an apoptotic effect in a variety of cells and is implicated in the pathogenesis of many disorders, including diabetic complications [20,21]. Nitric oxide reacts with superoxide to form the powerful oxidant, peroxynitrite (ONOO − ), which is thought to play a role in nitric oxidedependent cytotoxicity [22].…”