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• W2612157310 abstract "Objective— ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats-13) prevents microvascular thrombosis by cleaving prothrombogenic ultralarge von Willebrand factor (VWF) multimers. Clinical studies have found association between reduced ADAMTS13-specific activity, ultralarge VWF multimers, and thrombotic angiopathy in patients with diabetic nephropathy. It remains unknown, however, whether ADAMTS13 deficiency or ultralarge VWF multimers have a causative effect in diabetic nephropathy. Approach and Results— The extent of renal injury was evaluated in wild-type (WT), Adamts 13 −/− and Adamts 13 −/− Vwf −/− mice after 26 weeks of streptozotocin-induced diabetic nephropathy. We found that WT diabetic mice exhibited low plasma ADAMTS13-specific activity and increased VWF levels ( P <0.05 versus WT nondiabetic mice). Adamts 13 −/− diabetic mice exhibited deterioration of kidney function (increased albuminuria, plasma creatinine, and urea; P <0.05 versus WT diabetic mice), independent of hyperglycemia and hypertension. Deterioration of kidney function in Adamts 13 −/− diabetic mice was concomitant with aggravated intrarenal thrombosis (assessed by plasminogen activator inhibitor, VWF, fibrin(ogen), and CD41-positive microthrombi), increased mesangial cell expansion, and extracellular matrix deposition ( P <0.05 versus WT diabetic mice). Genetic deletion of VWF in Adamts 13 −/− diabetic mice improved kidney function, inhibited intrarenal thrombosis, and alleviated histological changes in glomeruli, suggesting that exacerbation of diabetic nephropathy in the setting of ADAMTS13 deficiency is VWF dependent. Conclusions— ADAMTS13 retards progression of diabetic nephropathy, most likely by inhibiting VWF-dependent intrarenal thrombosis. Alteration in ADAMTS13–VWF balance may be one of the key pathophysiological mechanisms of thrombotic angiopathy in diabetes mellitus." @default.
• W2612157310 created "2017-05-19" @default.
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• W2612157310 date "2017-07-01" @default.
• W2612157310 modified "2023-10-07" @default.
• W2612157310 title "ADAMTS13 Retards Progression of Diabetic Nephropathy by Inhibiting Intrarenal Thrombosis in Mice" @default.
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• W2612157310 doi "https://doi.org/10.1161/atvbaha.117.309539" @default.
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