Effect of pyridoxamine (K-163), an inhibitor of advanced glycation end products, on type 2 diabetic nephropathy in KK-Ay/Ta mice

Tanimoto, Masuhisa; Gohda, Tomohito; Kaneko, Shigeru; Hagiwara, Shinji; Murakoshi, Maki; Aoki, Tatsuya; Yamada, Kaori; Ito, Takamichi; Matsumoto, Mitsuhito; Horikoshi, Satoshi; Tomino, Yasuhiko

doi:10.1016/j.metabol.2006.08.026

Cited by 85 publications

(72 citation statements)

References 41 publications

(57 reference statements)

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“…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. 14 Despite the positive preclinical experience, we failed to show that Pyridorin altered the progressive loss of renal function anticipated in our patient population. Predefined secondary analyses did reveal data suggesting that patients with less severe renal damage may have responded to the drug.…”

Section: Discussionmentioning

confidence: 74%

“…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.…”

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confidence: 99%

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Pyridorin in Type 2 Diabetic Nephropathy

Lewis

Greene

Spitalewiz

et al. 2012

Journal of the American Society of Nephrology

135

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Pyridoxamine dihydrochloride (Pyridorin, NephroGenex) inhibits formation of advanced glycation end products and scavenges reactive oxygen species and toxic carbonyls, but whether these actions translate into renoprotective effects is unknown. In this double-blind, randomized, placebo-controlled trial, we randomly assigned 317 patients with proteinuric type 2 diabetic nephropathy to twice-daily placebo; Pyridorin, 150 mg twice daily; or Pyridorin, 300 mg twice daily, for 52 weeks. At baseline, the mean age 6 SD was 63.969.5 years, and the mean duration of diabetes was 17.668.5 years; the mean serum creatinine level was 2.260.6 mg/dl, and the mean protein-to-creatinine ratio was 297361932 mg/g. Regarding the primary end point, a statistically significant change in serum creatinine from baseline to 52 weeks was not evident in either Pyridorin group compared with placebo. However, analysis of covariance suggested that the magnitude of the treatment effect differed by baseline renal function. Among patients in the lowest tertile of baseline serum creatinine concentration, treatment with Pyridorin associated with a lower average change in serum creatinine concentration at 52 weeks (0.28, 0.07, and 0.14 mg/dl for placebo, Pyridorin 150 mg, and Pyridorin 300 mg, respectively; P=0.05 for either Pyridorin dose versus placebo); there was no evidence of a significant treatment effect in the middle or upper tertiles. In conclusion, this trial failed to detect an effect of Pyridorin on the progression of serum creatinine at 1 year, although it suggests that patients with less renal impairment might benefit.

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Section: Discussionmentioning

confidence: 74%

mentioning

confidence: 99%

Pyridorin in Type 2 Diabetic Nephropathy

Lewis

Greene

Spitalewiz

et al. 2012

Journal of the American Society of Nephrology

135

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“…Interestingly, elevated kynurenic acid in the urine is thought to be a consequence of reduced plasma vitamin B6 (73). It was recently reported that a mouse model (KK-Ay/Ta) with spontaneous T2DM showed significant improvements in several biochemical parameters as well as improved kidney function when fed a diet supplemented with pyridoxamine (a catalytically active amine form of vitamin B6) (74). The proposed mechanism is based on inhibition of advanced glycation end products by pyridoxamine (75).…”

Section: Discussionmentioning

confidence: 99%

Metabolomics Reveals Attenuation of the SLC6A20 Kidney Transporter in Nonhuman Primate and Mouse Models of Type 2 Diabetes Mellitus

Patterson

Bonzo

et al. 2011

Journal of Biological Chemistry

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To enhance understanding of the metabolic indicators of type 2 diabetes mellitus (T2DM) disease pathogenesis and progression, the urinary metabolomes of well characterized rhesus macaques (normal or spontaneously and naturally diabetic) were examined. High-resolution ultra-performance liquid chromatography coupled with the accurate mass determination of time-of-flight mass spectrometry was used to analyze spot urine samples from normal (n ‫؍‬ 10) and T2DM (n ‫؍‬ 11) male monkeys. The machine-learning algorithm random forests classified urine samples as either from normal or T2DM monkeys. The metabolites important for developing the classifier were further examined for their biological significance. Random forests models had a misclassification error of less than 5%. Metabolites were identified based on accurate masses (<10 ppm) and confirmed by tandem mass spectrometry of authentic compounds. Urinary compounds significantly increased (p < 0.05) in the T2DM when compared with the normal group included glycine betaine (9-fold), citric acid (2.8-fold), kynurenic acid (1.8-fold), glucose (68-fold), and pipecolic acid (6.5-fold). When compared with the conventional definition of T2DM, the metabolites were also useful in defining the T2DM condition, and the urinary elevations in glycine betaine and pipecolic acid (as well as proline) indicated defective re-absorption in the kidney proximal tubules by SLC6A20, a Na ؉ -dependent transporter. The mRNA levels of SLC6A20 were significantly reduced in the kidneys of monkeys with T2DM. These observations were validated in the db/db mouse model of T2DM. This study provides convincing evidence of the power of metabolomics for identifying functional changes at many levels in the omics pipeline.Type 2 diabetes mellitus (T2DM), 4 the most common type of diabetes, is a significant, costly, and rapidly expanding public health concern worldwide. T2DM is associated with microvascular (nephropathy, retinopathy, and neuropathy) and macrovascular (coronary artery disease and peripheral vascular disease) pathologies resulting in a complex, multifactorial metabolic phenotype. Therefore, understanding the molecular pathogenesis and progression of T2DM, its associated and varied complications, and its effects on numerous organ systems is not trivial. The emerging field of small molecule profiling, or metabolomics, has already provided new perspectives on T2DM (1-5). As the end products of all cellular processes, global metabolite profiling may represent the best and largest net with which to capture changes originating from epigenomic, genomic, transcriptomic, and proteomic alterations.Metabolomics aims to identify and quantify all small molecules as they may be the most accurate indicators of cellular physiology (6). Moreover, metabolomics is an NIH Roadmap Initiative and was listed as a research priority in the American Society of Nephrology Renal Research Report (7). Metabolomic studies of T2DM have utilized a variety of animal models (e.g. db/db mice, streptozotocin-treated mice, Zucker...

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“…The compounds are searched for, which could prevent the formation AGEs or eliminate their effect (Vasan et al 2003;Thomas et al 2005;Machado et al 2006;Coughlan et al 2007;Tanimoto et al 2007;Muellenbach et al 2008). One of these compounds is aminoguanidine (AG), which was, thanks to its effect, proposed for the prevention of diabetic complications (Giardino et al 1998;Gül et al 2008;Wu et al 2008).…”

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confidence: 99%

Influence of pyridoxylidene aminoguanidine on biomarkers of the oxidative stress and selected metabolic parameters of rats with diabetes mellitus

Országhová¹,

Liptáková²,

Muchová³

et al. 2009

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Abstract. Oxidative damage is considered to play an important role in the pathogenesis of several diseases, such as diabetes mellitus (DM), atherosclerosis, cardiovascular complications and chronic renal failure. DM is associated with the oxidative stress and formation of advanced glycation end products (AGEs). Different drugs inhibit oxidative stress and formation of advanced glycation end products. Aminoguanidine (AG) has been proposed as a drug of potential benefit in prophylaxis of the complications of DM. Recent reports show a pro-oxidant activity of AG. Therefore we examined the effect of structural analogue of AG, its Schiff base with pyridoxal -pyridoxylidene aminoguanidine (PAG) on the level of selected markers of oxidative stress. We found that PAG decreased total damage to DNA in controls as well as in diabetic group of rats. However, we also found that PAG supplementation increases susceptibility of lipoproteins to oxidation and formation of conjugated dienes in both, diabetic as well as control animals. Its administration to diabetic rats decreases antioxidant capacity of plasma. Therefore, it is necessary to search for other structural modifications of AG that would combine its higher anti-diabetic activity with less toxicity.

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Effect of pyridoxamine (K-163), an inhibitor of advanced glycation end products, on type 2 diabetic nephropathy in KK-Ay/Ta mice

Cited by 85 publications

References 41 publications

Pyridorin in Type 2 Diabetic Nephropathy

Pyridorin in Type 2 Diabetic Nephropathy

Metabolomics Reveals Attenuation of the SLC6A20 Kidney Transporter in Nonhuman Primate and Mouse Models of Type 2 Diabetes Mellitus

Influence of pyridoxylidene aminoguanidine on biomarkers of the oxidative stress and selected metabolic parameters of rats with diabetes mellitus

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