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Kidney Week

Abstract: FR-PO597

TMX-049, a Novel Xanthine Oxidase Inhibitor, Attenuates Renal Injury in an Experimental Model of Diabetic Kidney Disease

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Tsubosaka, Yoshiki, Teijin Pharma Limited, Tokyo, Japan
  • Shirakura, Takashi, Teijin Pharma Limited, Tokyo, Japan
  • Tsujimoto, Shunsuke, Teijin Pharma Limited, Tokyo, Japan
  • Aizawa, Reiko, Teijin Pharma Limited, Tokyo, Japan
  • Matsui, Chieko, Teijin Pharma Limited, Tokyo, Japan
  • Sakamoto, Yohei, Teijin Pharma Limited, Tokyo, Japan
  • Hase, Naoki, Teijin Pharma Limited, Tokyo, Japan
  • Kobayashi, Tsunefumi, Teijin Pharma Limited, Tokyo, Japan
Background

Diabetic kidney disease (DKD) is a major chronic renal complication of diabetes. Since several non-clinical and clinical studies imply the contribution of xanthine oxidase (XO) to the DKD progression, inhibiting XO activity may be one of the attractive therapeutic approaches. TMX-049 is a newly developed XO inhibitor with non-purine structure. In this study, we evaluate the effect of TMX-049 on renal damage in rat model of type 2 diabetes.

Methods

1. To examine the pharmacological profile of TMX-049, in vitro and in vivo inhibition of XO activity with TMX-049 treatment was measured in human primary hepatocyte and SD rat kidney, respectively. 2. To evaluate in vivo efficacy of TMX-049 on renal injury, 8 week-old male ZDF rats were orally administrated vehicle or TMX-049 once daily for 13 weeks. Normoglycemic ZDF-lean (ZL) rats were used as non-DKD control. The amount of urinary albumin and KIM-1, a biomarker for proximal tubular cell injury, were quantified on weeks 0, 2, 4, 6, 8, 10 and 12. Measurement of XO activity in renal cortex and histological analysis were determined at 13 weeks.

Results

1. TMX-049 inhibited cellular XO activity (IC50 = 2.43 ± 0.54 nM) in human hepatocyte and did not change other enzymatic activities related to purine metabolism. TMX-049 also showed sustained inhibition of XO activity in normal rat kidney 24 hours after oral administration, and its effect was more potent than that of launched XO inhibitor. 2. Compared with ZL rats, ZDF rats exhibited the renal structural changes, elevation of urinary parameters such as albumin and KIM-1 and increased XO activity in renal cortex. Immunohistological analysis revealed that XO/xanthine dehydrogenase expression was detected in the proximal tubules. Administration of TMX-049 reduced the urinary excretion of albumin and KIM-1, and ameliorated histological renal damage seen in ZDF rats without affecting any metabolic parameters.

Conclusion

TMX-049 attenuated renal injury in an experimental model of DKD. These results suggest the therapeutic potential of TMX-049 in DKD.