[PS 01-24] AN ORAL FACTOR XA INHIBITOR, EDOXABAN, ALLEVIATES DIABETIC NEPHROPATHY IN MICE LACKING eNOS

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Abstract

Objective:

Diabetic mice lacking endothelial NO synthase (eNOS, Nos3) develop advanced glomerular lesion, massive proteinuria, and hypertension that represent human diabetic nephropathy (DN). We recently reported that impaired eNOS upregulates coagulation tissue factor (TF) in diabetic kidney. TF activates coagulation factor X (FX) to FXa, which in turn stimulates protease-activated receptors (PARs) and causes inflammation.

Design and Method:

To elucidate the role of coagulation factor Xa in DN, we generated male diabetic mice lacking eNOS (Ins2Akita/+; Nos3-/-). At the age of 3 months, they were administered orally with FXa inhibitor (edoxaban, 50 mg/kg/day) to analyze at 6 months.

Results:

Renal FX mRNA, urinary FXa activity, and FX expression in glomerular macrophages were increased in DN. Administration of edoxaban ameliorated urinary albumin excretion and mesangial matrix expansion. The expression of Pars and of proinflammatory and profibrotic genes was also reduced. FXa induced inflammatory cytokines in endothelial cells and podocytes in vitro.

Conclusions:

We conclude that increased FXa exacerbates DN through inflammation, and that FXa is novel therapeutic target of DN.

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