Selective nanoparticle-mediated targeting of renal tubular Toll-like receptor 9 attenuates ischemic acute kidney injury

Sang Jun Han; Ryan M Williams; Vivette D'Agati; Edgar A Jaimes; Daniel A Heller; H Thomas Lee

doi:10.1016/j.kint.2020.01.036

Selective nanoparticle-mediated targeting of renal tubular Toll-like receptor 9 attenuates ischemic acute kidney injury

Kidney Int. 2020 Jul;98(1):76-87. doi: 10.1016/j.kint.2020.01.036. Epub 2020 Feb 22.

Authors

Sang Jun Han¹, Ryan M Williams², Vivette D'Agati³, Edgar A Jaimes⁴, Daniel A Heller⁵, H Thomas Lee⁶

Affiliations

¹ Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
² Department of Molecular Pharmacology & Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Biomedical Engineering, City College of New York, New York, New York, USA.
³ Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
⁴ Renal Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
⁵ Department of Molecular Pharmacology & Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
⁶ Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York, USA. Electronic address: tl128@columbia.edu.

Abstract

We developed an innovative therapy for ischemic acute kidney injury with discerning kidney-targeted delivery of a selective Toll-like receptor 9 (TLR9) antagonist in mice subjected to renal ischemia reperfusion injury. Our previous studies showed that mice deficient in renal proximal tubular TLR9 were protected against renal ischemia reperfusion injury demonstrating a critical role for renal proximal tubular TLR9 in generating ischemic acute kidney injury. Herein, we used 300-400 nm polymer-based mesoscale nanoparticles that localize to the renal tubules after intravenous injection. Mice were subjected to sham surgery or 30 minutes renal ischemia and reperfusion injury after receiving mesoscale nanoparticles encapsulated with a selective TLR9 antagonist (unmethylated CpG oligonucleotide ODN2088) or mesoscale nanoparticles encapsulating a negative control oligonucleotide. Mice treated with the encapsulated TLR9 antagonist either six hours before renal ischemia, at the time of reperfusion or 1.5 hours after reperfusion were protected against ischemic acute kidney injury. The ODN2088-encapsulated nanoparticles attenuated renal tubular necrosis, inflammation, decreased proinflammatory cytokine synthesis. neutrophil and macrophage infiltration and apoptosis, decreased DNA fragmentation and caspase 3/8 activation when compared to the negative control nanoparticle treated mice. Taken together, our studies further suggest that renal proximal tubular TLR9 activation exacerbates ischemic acute kidney injury by promoting renal tubular inflammation, apoptosis and necrosis after ischemia reperfusion. Thus, our studies suggest a potential promising therapy for ischemic acute kidney injury with selective kidney tubular targeting of TLR9 using mesoscale nanoparticle-based drug delivery.

Keywords: apoptosis; inflammation; ischemia and reperfusion injury; mesoscale nanoparticle; necrosis; neutrophil.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Acute Kidney Injury* / chemically induced
Acute Kidney Injury* / drug therapy
Acute Kidney Injury* / prevention & control
Animals
Apoptosis
Ischemia
Kidney
Kidney Tubules, Proximal
Mice
Mice, Inbred C57BL
Nanoparticles*
Reperfusion Injury* / drug therapy
Reperfusion Injury* / prevention & control
Toll-Like Receptor 9 / genetics

Substances

Tlr9 protein, mouse
Toll-Like Receptor 9

Abstract

Publication types

MeSH terms

Substances

Grants and funding