Effect of antioxidants and ACE inhibition on chemical modification of proteins and progression of nephropathy in the streptozotocin diabetic rat

Abstract

Aims/hypothesis. This study was designed to determine whether inhibition of formation of AGE and advanced lipoxidation end-products (ALE) is a mechanism of action common to a diverse group of therapeutic agents that limit the progress of diabetic nephropathy. We compared the effects of the ACE inhibitor enalapril, the antioxidant vitamin E, the thiol compound lipoic acid, and the AGE/ALE inhibitor pyridoxamine on the formation of AGE/ALE and protection against nephropathy in streptozotocin diabetic rats. Methods. Renal function and AGE/ALE formation were evaluated in rats treated with the agents listed above. Plasma was monitored monthly for triglycerides, cholesterol, creatinine and TNF-α, and 24-h urine samples were collected for measurement of albumin and total protein excretion. After 29 weeks, renal expression of mRNA for extracellular matrix proteins was measured, and AGE/ALE were quantified in skin and glomerular and tubular collagen. Results. Diabetic animals were both hyperglycaemic and dyslipidaemic, and showed evidence of early nephropathy (albuminuria, creatinaemia). All interventions limited the progression of nephropathy, without affecting glycaemia. The order of efficacy was: pyridoxamine (650 mg·kg −1 ·day −1 ) > vitamin E (200 mg·kg −1 ·day −1 ) > lipoic acid (93 mg·kg −1 ·day −1 ) enalapril (35 mg·kg −1 ·day −1 ). Pyridoxamine also significantly inhibited AGE/ALE accumulation in tissues; effects of other agents were mixed, but the degree of renoprotection was consistent with their effects on AGE/ALE formation. Conclusions/interpretation. All interventions inhibited the progression of nephropathy at the doses studied, but the maximal benefit was achieved with pyridoxamine, which also limited dyslipidaemia and AGE/ALE formation. These experiments indicate that the more effective the renoprotection, the greater the inhibition of AGE/ALE formation. For optimal protection of renal function, it would be beneficial to select drugs whose mechanism of action includes inhibition of AGE/ALE formation.

Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes

“…This is the first application of quantitative 'gold standard' stable isotopic dilution analysis LC-MS/MS to quantify a comprehensive range of glycation, oxidation and nitration adducts in tissues, plasma and urine in experimental diabetes. Independent MS estimates of CML residues of renal glomeruli [22] and immunoassay of CML content of plasma protein of healthy control rats [23] were in agreement with estimates herein. Immunoassay of AGEs in tissue, however, has overestimated increases in experimental diabetes [4,5,24].…”

Pyridorin in Type 2 Diabetic Nephropathy

“…Elevation in serum creatinine concentrations and increased urine albumin excretion in rats with streptozotocin-induced diabetes were diminished in animals treated for 30 weeks. 10,11 Pyridorin also inhibited formation of advanced glycation and lipoxidation end products and controlled plasma lipids, while limiting the loss of renal function and reducing albuminuria in Zucker rats. 12 Progression of diabetic glomerular histopathologic findings over 15 weeks of therapy decreased in db/db diabetic mice, 13 and improved albuminuria was reported in the KK-A y /Ta mouse model of diabetic nephropathy.…”

“…Several preclinical studies in rat models of diabetic nephropathy have demonstrated oral Pyridorin to be efficacious in preserving renal function. [10][11][12][13][14] Two small, 24-week clinical safety trials have reported an apparent decrease in the rate of loss of renal function associated with Pyridorin treatment. 15 The purpose of our study was to determine whether 1 year of therapy with Pyridorin delayed the progressive loss of renal function in patients with type 2 diabetes mellitus and advanced nephropathy.…”

Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products

“…Pyridoxamine also prevents ALE formation in diabetic and obese rats [36,37] through cleavage of alpha-dicarbonyl intermediates in glycoxidation and lipoxidation reactions [38]. It also effectively reduced upregulation of retinal haemoxygenase-1, which is significant as this enzyme has been previously used as a reliable marker of oxidative stress in diabetic retinopathy [25,26].…”