Sustained local inhibition of thrombin preserves renal microarchitecture and function after onset of acute kidney injury
Year: 2021
Type: article
Abstract: Acute kidney injury (AKI) management remains mainly supportive as no specific therapeutic agents directed at singular signaling pathways have succeeded in clinical trials. Here, we report that inhibition of thrombin-driven clotting and inflammatory signaling with use of locally-acting thrombin-targeted perfluorocarbon nanoparticles (PFC NP) protects renal vasculature and broadly modulates diverse inflammatory processes that cause renal ischemia reperfusion injury. Each PFC NP was complexed with ~13,650 copies of the direct thrombin inhibitor, PPACK (proline-phenylalanine-arginine-chloromethyl-ketone). Mice treated after the onset of AKI with PPACK PFC NP exhibited downregulated VCAM-1, ICAM-1, PGD2 prostanoid, M-CSF, IL-6, and mast cell infiltrates. Microvascular architecture, tubular basement membranes, and brush border components were better preserved. Non-reperfusion was reduced as indicated by reduced red blood cell trapping and non-heme iron. Kidney function and tubular necrosis improved at 24 hours versus the untreated control group, suggesting a benefit for dual inhibition of thrombosis and inflammation by PPACK PFC NP.
Language: English
Topic: Acute Kidney Injury Research
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,220
Funders: U.S. Department of Veterans Affairs, California Energy Commission, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1503134167, iPLA2beta-mediated alternative splicing and beta-cell death in type 1 diabetes, The utilization of photonics technology to rapidly detect bioactive lipids associated with preeclampsia development, Anti-Inflammatory Therapeutics for Cardiovascular Disease, Inhibition of NF-kB with siRNA/Peptide Nanoparticles for Arthritis Treatment, The functional role of the cPLA2alpha/C1P interaction in sepsis resolution, The role of ceramide kinase in mitophagy, The role and mechanistic regulation of cPLA2alpha in eicosanoid biosynthesis and wound healing, G4670433464, Prevention and Treatment of Acute Kidney Injury, G7583639016, G8173979607, Mitigate cisplatin induced acute kidney injury through preservation of vasculature and proximal tubule, G8532398431, The roles of ceramide and its derivatives in A. phagocytophilum pathogenesis
OpenAlex ID: W3184411186