title: Antithrombin nanoparticles improve kidney reperfusion and protect kidney function after ischemia-reperfusion injury.
abstract: In the extension phase of acute kidney injury, microvascular thrombosis, inflammation, vasoconstriction, and vascular endothelial cell dysfunction promote progressive damage to renal parenchyma after reperfusion. In this study, we hypothesized that direct targeting and pharmaceutical knockdown of activated thrombin at the sites of injury with a selective nanoparticle (NP)-based thrombin inhibitor, PPACK (phenylalanine-proline-arginine-chloromethylketone), would improve kidney reperfusion and protect renal function after transient warm ischemia in rodent models. Saline- or plain NP-treated animals were employed as controls. In vivo 19F magnetic resonance imaging revealed that kidney nonreperfusion was evident within 3 h after global kidney reperfusion at 34 ± 13% area in the saline group and 43 ± 12% area in the plain NP group and substantially reduced to 17 ± 4% (∼50% decrease, P < 0.05) in the PPACK NP pretreatment group. PPACK NP pretreatment prevented an increase in serum creatinine concentration within 24 h after ischemia-reperfusion, reflecting preserved renal function. Histologic analysis illustrated substantially reduced intrarenal thrombin accumulation within 24 h after reperfusion for PPACK NP-treated kidneys (0.11% ± 0.06%) compared with saline-treated kidneys (0.58 ± 0.37%). These results suggest a direct role for thrombin in the pathophysiology of AKI and a nanomedicine-based preventative strategy for improving kidney reperfusion after transient warm ischemia.
authors: Department of Medicine, Washington University, St. Louis, Missouri;
authors: Junjie
authors: J
authors: Chen
authors: Department of Medicine, Washington University, St. Louis, Missouri; Department of Surgery, Washington University, St. Louis, Missouri;
authors: Chandu
authors: C
authors: Vemuri
authors: Department of Medicine, Washington University, St. Louis, Missouri; Department of Biomedical Engineering, Washington University, St. Louis, Missouri; and.
authors: Rohun U
authors: RU
authors: Palekar
authors: Department of Pathology and Immunology, Washington University, St. Louis, Missouri.
authors: Joseph P
authors: JP
authors: Gaut
authors: Department of Medicine, Washington University, St. Louis, Missouri; Department of Biomedical Engineering, Washington University, St. Louis, Missouri; and.
authors: Matthew
authors: M
authors: Goette
authors: Department of Medicine, Washington University, St. Louis, Missouri;
authors: Lingzhi
authors: L
authors: Hu
authors: Department of Medicine, Washington University, St. Louis, Missouri;
authors: Grace
authors: G
authors: Cui
authors: Department of Medicine, Washington University, St. Louis, Missouri;
authors: Huiying
authors: H
authors: Zhang
authors: Department of Medicine, Washington University, St. Louis, Missouri; Department of Biomedical Engineering, Washington University, St. Louis, Missouri; and saw@wuphysics.wustl.edu.
authors: Samuel A
authors: SA
authors: Wickline
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000473:pathology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003404:Creatinine / Q000652:urine; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy; D058185:Magnetite Nanoparticles / Q000008:administration & dosage*; D008297:Male; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D058185:Magnetite Nanoparticles; D003404:Creatinine; D013917:Thrombin; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone
keywords: MRI; acute kidney injury; anticoagulation; nanoparticles
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