ADAMTS13 Retards Progression of Diabetic Nephropathy by Inhibiting Intrarenal Thrombosis in Mice. Issue 7 (July 2017)

• Record Type: Journal Article
• Authors: Dhanesha, Nirav; Doddapattar, Prakash; Chorawala, Mehul R.; Nayak, Manasa K.; Kokame, Koichi; Staber, Janice M.; Lentz, Steven R.; Chauhan, Anil K.
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 37:Issue 7(2017)
• Publication Date: 2017-07
• Subjects: albuminuria -- diabetic nephropathy -- streptozotocin -- thrombosis -- von Willebrand factor; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.117.309539
• Languages: English
• ISSNs: 1079-5642

Abstract

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. Abstract : Supplemental Digital Content is available in the text.