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Abstract: TH-PO892

Different Renoprotective Mechanism of TMX-049, a Novel Xanthine Oxidoreductase Inhibitor, from Losartan: The Importance of Renal Tubule for Diabetic Kidney Disease Treatment

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

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

Diabetic kidney disease (DKD) is a major renal complication of diabetes. Although the glomerulus has been considered as the primary site of injury, recent studies have suggested that renal tubule is also the prominent site. Current medications such as losartan (Los) exert the renoprotective effects by reducing intraglomerular pressure. However, there is no drug which targets tubular injury. Xanthine oxidoreductase (XOR) is an enzyme producing uric acid and its inhibitors have been reported to improve albuminuria in DKD patients. To date we found that XOR is mainly expressed in renal tubule in rats, suggesting the target site of XOR inhibitor may be renal tubule. To determine the renoprotective effect of TMX-049, a novel XOR inhibitor, and the importance of renal tubule as a target site for DKD treatment, we examined them using animal models of DKD and albumin-induced tubular injury.

Methods

1. Male ZDF rats were orally administrated TMX-049 or Los for 13 weeks. 2. Male unilateral nephrectomized rats were intraperitoneally injected with bovine serum albumin and orally administrated with TMX-049 or Los for 3 weeks. Urinary albumin, and KIM-1 as a tubular injury marker, were measured. XOR activity in the renal cortex was measured and histological and immunohistochemical analyses were performed.

Results

XOR, mainly expressed in renal tubule, was increased in ZDF rats, consistent with the increased XOR activity in renal cortex. TMX-049 but not Los inhibited XOR activity. In addition, TMX-049 as well as Los decreased urinary albumin and KIM-1 excretions, and ameliorated histological damage in both glomerular and tubular region in ZDF rats. Albumin induced the damage in tubular region and urinary KIM-1 excretion, indicating tubular injury by albumin, while there were no changes in glomerular region. Consistent with ZDF rats, XOR activity in renal cortex was increased in albumin-treated rats. Importantly, TMX-049 attenuated albumin-induced tubular damages whereas Los failed.

Conclusion

TMX-049 attenuated renal tubular damage by inhibiting tubular XOR, leading to suppress renal injury. These results suggest the therapeutic potential of TMX-049 and the importance of renal tubule as a target site for DKD treatment.