Non-purine selective xanthine oxidase inhibitor ameliorates glomerular endothelial injury in InsAkitadiabetic mice

Seiji Itano, Hiroyuki Kadoya*, Minoru Satoh, Takashi Nakamura, Takayo Murase, Tamaki Sasaki, Yashpal S. Kanwar, Naoki Kashihara

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Endothelial dysfunction represents a predominant early feature of diabetes, rendering patients with diabetes prone to renal complications, e.g., proteinuria. Recent studies have indicated a possible role for xanthine oxidase (XO) in the pathogenesis of vascular dysfunctions associated with diabetes. In the present study, we investigated the contribution of XO activation on the progression of diabetic nephropathy in a mouse model using selective XO inhibitors. Male Ins2Akita heterozygous mice were used with wild-type mice as controls. Akita mice were treated with topiroxostat (Topi) or vehicle for 4 wk. Serum uric acid levels were significantly reduced in Akita + Topi mice compared with Akita + vehicle mice. The Akita + Topi group had a significant reduction in urinary albumin excretion compared with the Akita + vehicle group. Mesangial expansion, glomerular collagen type IV deposition, and glomerular endothelial injury (assessed by lectin staining and transmission electron microscopy) were considerably reduced in the Akita + topi group compared with the Akita + vehicle group. Furthermore, glomerular permeability was significantly higher in the Akita + vehicle group compared with the wild-type group. These changes were reduced with the administration of Topi. We conclude that XO inhibitors preserve glomerular endothelial functions and rescue compromised glomerular permeability, suggesting that XO activation plays a vital role in the pathogenesis of diabetic nephropathy.

Original languageEnglish (US)
Pages (from-to)F765-F722
JournalAmerican Journal of Physiology - Renal Physiology
Volume319
Issue number5
DOIs
StatePublished - Nov 2020

Keywords

  • Diabetic nephropathy
  • Endothelial dysfunction
  • Glycocalyx
  • In vivo imaging
  • Xanthine oxidase

ASJC Scopus subject areas

  • Physiology
  • Urology

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