Journal article
ADAMTS13 Retards Progression of Diabetic Nephropathy by Inhibiting Intrarenal Thrombosis in Mice
Arteriosclerosis, thrombosis, and vascular biology, Vol.37(7), pp.1332-1338
07/2017
DOI: 10.1161/ATVBAHA.117.309539
PMCID: PMC5501287
PMID: 28495930
Abstract
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.
The extent of renal injury was evaluated in wild-type (WT),
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and
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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 (
<0.05 versus WT nondiabetic mice).
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diabetic mice exhibited deterioration of kidney function (increased albuminuria, plasma creatinine, and urea;
<0.05 versus WT diabetic mice), independent of hyperglycemia and hypertension. Deterioration of kidney function in
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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 (
<0.05 versus WT diabetic mice). Genetic deletion of VWF in
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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.
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.
Details
- Title: Subtitle
- ADAMTS13 Retards Progression of Diabetic Nephropathy by Inhibiting Intrarenal Thrombosis in Mice
- Creators
- Nirav Dhanesha - From the Department of Internal Medicine (N.D., P.D., M.R.C., M.K.N., S.R.L., A.K.C.) and Stead Family Department of Pediatrics (J.M.S.), University of Iowa; and Department of Molecular Pathogenesis, National Cardiovascular Centre Research Institute, Suita, Osaka, Japan (K.K.)Prakash Doddapattar - From the Department of Internal Medicine (N.D., P.D., M.R.C., M.K.N., S.R.L., A.K.C.) and Stead Family Department of Pediatrics (J.M.S.), University of Iowa; and Department of Molecular Pathogenesis, National Cardiovascular Centre Research Institute, Suita, Osaka, Japan (K.K.)Mehul R Chorawala - From the Department of Internal Medicine (N.D., P.D., M.R.C., M.K.N., S.R.L., A.K.C.) and Stead Family Department of Pediatrics (J.M.S.), University of Iowa; and Department of Molecular Pathogenesis, National Cardiovascular Centre Research Institute, Suita, Osaka, Japan (K.K.)Manasa K Nayak - From the Department of Internal Medicine (N.D., P.D., M.R.C., M.K.N., S.R.L., A.K.C.) and Stead Family Department of Pediatrics (J.M.S.), University of Iowa; and Department of Molecular Pathogenesis, National Cardiovascular Centre Research Institute, Suita, Osaka, Japan (K.K.)Koichi Kokame - From the Department of Internal Medicine (N.D., P.D., M.R.C., M.K.N., S.R.L., A.K.C.) and Stead Family Department of Pediatrics (J.M.S.), University of Iowa; and Department of Molecular Pathogenesis, National Cardiovascular Centre Research Institute, Suita, Osaka, Japan (K.K.)Janice M Staber - From the Department of Internal Medicine (N.D., P.D., M.R.C., M.K.N., S.R.L., A.K.C.) and Stead Family Department of Pediatrics (J.M.S.), University of Iowa; and Department of Molecular Pathogenesis, National Cardiovascular Centre Research Institute, Suita, Osaka, Japan (K.K.)Steven R Lentz - From the Department of Internal Medicine (N.D., P.D., M.R.C., M.K.N., S.R.L., A.K.C.) and Stead Family Department of Pediatrics (J.M.S.), University of Iowa; and Department of Molecular Pathogenesis, National Cardiovascular Centre Research Institute, Suita, Osaka, Japan (K.K.)Anil K Chauhan - From the Department of Internal Medicine (N.D., P.D., M.R.C., M.K.N., S.R.L., A.K.C.) and Stead Family Department of Pediatrics (J.M.S.), University of Iowa; and Department of Molecular Pathogenesis, National Cardiovascular Centre Research Institute, Suita, Osaka, Japan (K.K.). anil-chauhan@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.37(7), pp.1332-1338
- Publisher
- United States
- DOI
- 10.1161/ATVBAHA.117.309539
- PMID
- 28495930
- PMCID
- PMC5501287
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Grant note
- R01 HL118246 / NHLBI NIH HHS R01 HL118742 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS
- Language
- English
- Date published
- 07/2017
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Hematology/Oncology; Internal Medicine
- Record Identifier
- 9984070995002771
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