Aminoguanidine inhibits albuminuria, but not the formation of advanced glycation end-products in skin collagen of diabetic rats

Degenhardt, Thorsten P.; Fu, Min-Xin; Voß, Edgar; Reiff, K.; Neidlein, R.; Strein, K.; Thorpe, Suzanne R.; Baynes, John W.; Reiter, Rudolf

doi:10.1016/s0168-8227(98)00121-1

Cited by 29 publications

(20 citation statements)

References 46 publications

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“…Therefore, this study included analysis of glycated haemoglobin, the AGE precursor fructose lysine (FL) and well characterised AGEs such as pentosidine, CML and CEL in skin collagen. In agreement with previous work in diabetic rats [33] and with earlier studies on the effect of caloric restriction in rats . There is a significant increase in BM volume when nondiabetic control retinal capillaries are compared to diabetic control animals (***p<0.001).…”

Section: Discussionsupporting

confidence: 93%

“…The increase in CEL is consistent with an increase in carbohydrate flux to triose phosphates via glycolysis and the reported increase in methylglyoxal concentration in blood of diabetic animals [36,37]. Similar relative responses of pentosidine, CML and CEL in skin collagen have been observed in studies of STZ-diabetic rats and CML and CEL, but not pentosidine were decreased by the AGE inhibitor pyridoxamine [31,33]. Despite inhibiting of BM thickening in the current study, Sulindac had no effect on glycation of haemoglobin, FL or AGE-modification of skin collagen.…”

Section: Discussionsupporting

confidence: 84%

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Prevention of retinal capillary basement membrane thickening in diabetic dogs by a non-steroidal anti-inflammatory drug

et al. 2003

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Aims/hypothesis. To investigate the effect of treatment with the non-steroidal anti-inflammatory drug Sulindac on the early vascular pathology of diabetic retinopathy in the dog, and it's effect on recognised biochemical indices of hyperglycaemia-related pathophysiology. Methods. Experimental diabetes (streptozotocin/alloxan) was induced in 22 male beagle dogs and 12 of the animals were assigned at random to receive oral Sulindac (10 mg/kg daily). Age-and sex-matched control animals were maintained as non-diabetic controls. After 4 years, several morphological parameters were quantified in the retinal microvasculature of each animal group using an established stereological method. Also, the following diabetes-associated biochemical parameters were analysed: accumulation of advanced glycation end products (AGEs), red blood cell polyol levels and antioxidant status. Results. Diabetes increased red blood cell sorbitol levels when compared to non-diabetic controls (p≤0.05), however, there was no difference in sorbitol levels between the untreated and the treated diabetic animals. No significant differences were found in red blood cell myoinositol levels between the three groups of animals. Pentosidine and other AGEs were increased two-to three-fold in the diabetic animals (p≤0.001) although treatment with Sulindac did not affect their accumulation in diabetic skin collagen or alter diabetesinduced rises in plasma malondialdehyde. Retinal capillary basement membrane volume was significantly increased in the untreated diabetic dogs compared to non-diabetic controls or Sulindac-treated diabetic animals (p≤0.0001). Conclusion/interpretation. This study has confirmed the beneficial effect of a non-steroidal anti-inflammatory drug on the early vascular pathology of diabetic retinopathy. However the treatment benefit was not dependent on inhibition of polyol pathway activity, advanced glycation, or oxidative stress. [Diabetologia (2003[Diabetologia ( ) 46:1269[Diabetologia ( -1275

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 84%

Prevention of retinal capillary basement membrane thickening in diabetic dogs by a non-steroidal anti-inflammatory drug

et al. 2003

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“…The Schiff base product of this reaction rearranges to an Amadori intermediate that, in turn, is converted to AGEs (see Fig. 7, step 1), most prominently to CML (13), which is detected at an increased concentration in animal and human tissues in diabetes, neurodegenerative diseases, and aging (45)(46)(47)(48). AGE modifications have been implicated as a source of structural and functional damage of proteins in diseases such as diabetes (49 - 7).…”

Section: Discussionmentioning

confidence: 99%

A Post-Amadori Inhibitor Pyridoxamine Also Inhibits Chemical Modification of Proteins by Scavenging Carbonyl Intermediates of Carbohydrate and Lipid Degradation

Voziyan

Metz

Baynes

et al. 2002

Journal of Biological Chemistry

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204

202

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Reactive carbonyl compounds are formed during autoxidation of carbohydrates and peroxidation of lipids. These compounds are intermediates in the formation of advanced glycation end products (AGE) and advanced lipoxidation end products (ALE) in tissue proteins during aging and in chronic disease. We studied the reaction of carbonyl compounds glyoxal (GO) and glycolaldehyde (GLA) with pyridoxamine (PM), a potent postAmadori inhibitor of AGE formation in vitro and of development of renal and retinal pathology in diabetic animals. PM reacted rapidly with GO and GLA in neutral, aqueous buffer, forming a Schiff base intermediate that cyclized to a hemiaminal adduct by intramolecular reaction with the phenolic hydroxyl group of PM. This bicyclic intermediate dimerized to form a five-ring compound with a central piperazine ring, which was characterized by electrospray ionization-liquid chromatography/mass spectrometry, NMR, and x-ray crystallography. PM also inhibited the modification of lysine residues and loss of enzymatic activity of RNase in the presence of GO and GLA and inhibited formation of the AGE/ALE N ⑀ -(carboxymethyl)lysine during reaction of GO and GLA with bovine serum albumin. Our data suggest that the AGE/ALE inhibitory activity and the therapeutic effects of PM observed in diabetic animal models depend, at least in part, on its ability to trap reactive carbonyl intermediates in AGE/ALE formation, thereby inhibiting the chemical modification of tissue proteins.

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“…One major effect of AG is to inhibit the formation of AGE, which results from nonenzymatic glycation of proteins, especially those taking part in the structure of tissues. This reaction has been postulated as a central mechanism in the pathogenesis of progressive nephropathies secondary to diabetes mellitus and aging, and could explain the beneficial effects of AG in these conditions, although this hypothesis has been disputed (25,26). In this study, however, the protective effect of AG can hardly be attributed to the prevention of AGE formation: the Nx model is not associated with a tendency toward increased nonenzymatic glycation of proteins, as indicated by the similar levels of Hb A1c observed in the sham, Nx, and NxϩAG groups.…”

Section: Discussionmentioning

confidence: 99%

“…The exact mechanism underlying these protective effects is unclear. Although some investigators believe that AG works by inhibiting the formation of advanced glycation end products (AGE) (23,24), at least in diabetic and aging nephropathies, others contend that the beneficial effect of AG may be entirely due to an antiinflammatory effect, resulting from its inhibition of the inducible isoform of the nitric oxide synthase (iNOS) (25,26).…”

mentioning

confidence: 99%

Evidence for the Existence of Two Distinct Functions for the Inducible NO Synthase in the Rat Kidney

Fujihara¹,

Mattar²,

Vieira³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. The functional role of the NO synthase (NOS) isoforms in the normal or diseased kidney is uncertain. This study examined the renal expression of the endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) isoforms by both immunohistochemistry and Western blot analyses in shamoperated rats (S) and in rats subjected to 5/6 nephrectomy (Nx). Primary antibodies from two different sources were used to detect iNOS. Additional S and Nx rats were chronically treated with aminoguanidine (AG), a selective iNOS inhibitor. All three isoforms were clearly expressed in S kidney. Their renal abundance, evaluated by Western blot analysis, fell in Nx rats. With the use of anti-iNOS antibodies from two distinct sources, the immunohistochemical analysis showed the presence of what appeared to be two distinct iNOS fractions: a "tubular" fraction, present in S and with decreased intensity in Nx; and an "interstitial" fraction, observed only in inflamed areas of Nx rats. AG treatment greatly attenuated renal injury in Nx rats by a direct antiinflammatory effect, likely related to iNOS inhibition, rather than to amelioration of renal hemodynamics or to reduced protein glycation. These observations suggest that: (1) the functional role of the renal iNOS isoform may vary dramatically under different physiologic conditions; (2) caution should be taken in the interpretation of immunohistochemical iNOS data, because antibodies from different sources may detect different iNOS fractions; and (3) AG treatment may become useful in the treatment of human progressive nephropathies, even those not associated with diabetes or aging.

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Aminoguanidine inhibits albuminuria, but not the formation of advanced glycation end-products in skin collagen of diabetic rats

Cited by 29 publications

References 46 publications

Prevention of retinal capillary basement membrane thickening in diabetic dogs by a non-steroidal anti-inflammatory drug

Prevention of retinal capillary basement membrane thickening in diabetic dogs by a non-steroidal anti-inflammatory drug

A Post-Amadori Inhibitor Pyridoxamine Also Inhibits Chemical Modification of Proteins by Scavenging Carbonyl Intermediates of Carbohydrate and Lipid Degradation

Evidence for the Existence of Two Distinct Functions for the Inducible NO Synthase in the Rat Kidney

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