ISH NIA PS 01-07 Possible implication of xanthine oxidase activation on the pathogenesis diabetic nephropathy

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Abstract

Objective:

Endothelial dysfunction represents a predominant early feature of diabetes and makes diabetic patients prone to renal complications. Recent evidence has indicated possible role of xanthine oxidase (XO) in the pathogenesis of vascular dysfunction associated with diabetes. However, it is not clear whether XO activity is involved in pathogenesis of diabetic nephropathy (DN). We investigated the contribution of XO activation on the progression of mouse DN by selective XO inhibitors, Topiroxostat (Top) and Febuxostat (Feb).

Design and Method:

Male Ins2Akita heterozygote (Akita; 10 weeks old) mice were used. Wild-type (WT) mice were used for control. Akita mice were treated with Top (3 mg/kg/day), Feb (1 mg/kg/day) or Vehicle (Vehi) for 4weeks. Serum uric acid and urinary albumin excretion (UAE) were measured. Glomerular pathological changes were also examined by light microscope and electron microscope. Glomerular permeability was assessed using 2 photon microscopy and fluorescent labeling albumin.

Results:

Serum uric acid levels showed no significant difference between all groups. Akita + Top or Akita + Feb groups showed significant reduction of UAE in comparison with Akita + Vehi group. Mesangial expansion, glomerular collagen IV deposition, and glomerular endothelial injury (examined by lectin stain and transmission electron microscope) were ameliorated in Akita + Top or Akita + Feb group compared with Akita + Vehi group. Furthermore, glomerular permeability was deteriorated in Akita + Vehi group compared with WT group. These changes were ameliorated with addition of Top or Feb.

Conclusions:

XO inhibitors preserved glomerular endothelial function and improved deteriorated glomerular permeability, indicating that XO activation is involved in pathogenesis of DN.

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