Renoprotective effect of topiroxostat via antioxidant activity in puromycin aminonucleoside nephrosis rats.

Abstract

Topiroxostat is a novel inhibitor of xanthine oxidase, and is postulated to exert a renoprotective effect. Puromycin aminonucleoside nephrosis (PAN) is a rat model of minimal change nephrotic syndrome. In this study, we examined whether topiroxostat ameliorates the kidney injury in PAN rats that was induced by a single intraperitoneal injection of PA (100 mg/kg body weight). Rats were divided into four groups: control rats, PAN rats, control rats treated with topiroxostat (1.0 mg/kg/day), and PAN rats treated with topiroxostat. Topiroxostat significantly reduced the amount of uric acid in the kidney cortex, while serum UA concentration remained unaffected by this treatment. Urinary protein excretion decreased significantly on day 10 in PAN rats upon topiroxostat treatment. Podocyte injury in PAN rats, as indicated by the reduction in WT-1-positive cell numbers and podocin immunoreactivity and foot process effacement, was partially yet significantly alleviated with topiroxostat treatment. In the kidney cortex, the increase in oxidative stress markers such as nitrotyrosine and 8-hydroxy-2-deoxyguanosine (8-OHdG) and the enhanced expressions of xanthine oxidase and NADPH oxidase 4 (NOX4) in PAN rats were significantly ameliorated by topiroxostat. Using cultured podocytes NOX4 expression was upregulated by adding 12 mg/dL UA into the culture medium. These results suggest that topiroxostat ameliorates proteinuria and kidney injury in PAN rats by lowering oxidative stress and tissue UA concentration. The renoprotective effects of topiroxostat could be attributed to its potential to inhibit xanthine oxidase and NOX4 in concert with suppression of intracellular UA production.

• Authors: Yosuke Kawamorita, Takeshi Shiraishi, Yoshifuru Tamura, Takanori Kumagai, Shigeru Shibata, Yoshihide Fujigaki, Makoto Hosoyamada, Takahiko Nakagawa, Shunya Uchida
• Journal: Physiological reports (Physiol Rep) Vol. 5 Issue 15 (Aug 2017) ISSN: 2051-817X [Electronic] United States
• PMID: 28774949 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Chemical References

• Antioxidants
• Enzyme Inhibitors
• Nitriles
• Pyridines
• FYX-051
• Uric Acid
• Puromycin Aminonucleoside
• 8-Hydroxy-2'-Deoxyguanosine
• NADPH Oxidase 4
• Nox4 protein, rat
• Deoxyguanosine

Topics

• 8-Hydroxy-2'-Deoxyguanosine
• Animals
• Antioxidants (administration & dosage, pharmacology, therapeutic use)
• Cell Line
• Deoxyguanosine (analogs & derivatives, metabolism)
• Enzyme Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Kidney (drug effects, metabolism)
• Male
• Mice
• NADPH Oxidase 4 (metabolism)
• Nephrosis (drug therapy, etiology)
• Nitriles (administration & dosage, pharmacology, therapeutic use)
• Oxidative Stress
• Podocytes (drug effects, metabolism)
• Puromycin Aminonucleoside (toxicity)
• Pyridines (administration & dosage, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Uric Acid (metabolism)