Abstract: FR-PO356

Xanthine Oxidoreductase Inhibitor, Topiroxostat, Had a Renoprotective Role under Decreased Angiotensin II Type 1a Receptor Expression

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Ikemori, Atsuko, St. Marianna University School, Kawasaki, Kanagawa, Japan
  • Sugaya, Takeshi, St. Marianna Univ, Tokyo, Japan
  • Hisamichi, Mikako, St.Marianna university school of medicine, Kawasaki, Japan
  • Kimura, Kenjiro, Tokyo Takanawa Hospital, Tokyo, Japan
  • Shibagaki, Yugo, Division of Nephrology and Hypertension, St Marianna University Hospital, Kawasaki, Japan
Background

Xanthine oxidoreductase (XOR) inhibitors may function as renoprotective agents as well as antioxidants via decrease in oxidative stress produced by renal xanthine oxidase converted from XOR. The aim of this study was to confirm the renoprotective effect of the XOR inhibitor, topiroxostat (Top) under decreased angiotensin II type 1a (AT1a) receptor expression in the model of renal injury caused by adenine.

Methods

To evaluate the degree of tubular damage using urinary liver-type fatty acid-binding protein (L-FABP) under decreased AT1a expression, we used AT1a receptor knockdown hetero and human L-FABP chromosomal transgenic (Tg) mice (AT1a+/-L-FABP+/-). Male AT1a+/-L-FABP+/- mice were divided into two groups: the adenine diet group (n=24) was given a diet containing only 0.2% w/w adenine, and the normal diet group (n=5) was given a normal diet. When renal dysfunction was confirmed in the adenine diet group 4 weeks after starting the diet, the adenine diet group was further divided into three groups. The adenine diet group (n=8) was continuously given only the adenine diet. Each group receiving high-dose (3mg/kg) or low-dose (1mg/kg) Top (Top-H, n=8, Top-L, n=8) was given the adenine diet including the drug for another 4 weeks.

Results


The levels of renal XOR, renal dysfunction, urinary L-FABP, tubulointerstitial damage, hypoxia, and oxidative stress were decreased or attenuated after treatment with Top compared with the adenine diet group.

Conclusion


In conclusion, Top attenuated renal damage under decreased AT1a expression in the adenine-induced renal injury model. Combination treatment with an XOR inhibitor and an RAS inhibitor might be a useful strategy for prevention of the progression of CKD.

Funding

  • Commercial Support