Abstract
Objective: Coagulation factors VIIa and Xa activate protease-activated receptor 2 (PAR2), which induces inflammation. Although PAR2 is reportedly rich in the kidney and up-regulated under diabetic condition, its role in diabetic nephropathy (DN) is unclear. Design and Method: We generated male diabetic mice lacking Par2 (Ins2Akita/+; Nos+/−; Par2−/−) to compare wild-type Par2 mice (Ins2Akita/+; Nos+/−; Par2+/+), and harvested their tissue and plasma samples at 7 months old. Results: Gene expression of Par2 was markedly increased in DN. Lack of Par2 ameliorated urinary albumin excretion, mesangial matrix expansion, and tubular atrophy together with reduction of proinflammatory and profibrotic gene expression in the kidney. Thickening of glomerular basement membrane and foot process effacement were also ameliorated. PAR2 agonist (2f-LIGRLO) directly induces Mcp1 and Ptgs2 (encoding COX2) mRNA in murine podocyte. Conclusions: We conclude that elevated PAR2 signaling exacerbates DN. PAR2 is a novel therapeutic target of DN.
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