ADAMTS13 Retards Progression of Diabetic Nephropathy by Inhibiting Intrarenal Thrombosis in Mice.

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.