Sustained local inhibition of thrombin preserves renal microarchitecture and function after onset of acute kidney injury

Ian Vargas, Daniel J. Stephenson, Margaret Baldwin, Joseph Gaut, Charles E. Chalfant, Hua Pan, Samuel A. Wickline

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number102449
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume38
DOIs
StatePublished - Nov 2021

Keywords

  • Acute kidney injury
  • Inflammation
  • Perfluorocarbon nanoparticles
  • Thrombosis
  • Vessel damage

Fingerprint

Dive into the research topics of 'Sustained local inhibition of thrombin preserves renal microarchitecture and function after onset of acute kidney injury'. Together they form a unique fingerprint.

Cite this