Renal proximal tubular NEMO plays a critical role in ischemic acute kidney injury

Authors

Sang Jun Han, Columbia University
Ryan M. Williams, CUNY City CollegeFollow
Mihwa Kim, Columbia University
Daniel A. Heller, Memorial Sloan Kettering Cancer Center
Vivette D'Agati, Columbia University
Marc Schmidt-Supprian, Technical University Munich
H. Thomas Lee, Columbia University

Document Type

Article

Publication Date

9-17-2020

Abstract

We determined that renal proximal tubular (PT) NF-κB essential modulator (NEMO) plays a direct and critical role in ischemic acute kidney injury (AKI) using mice lacking renal PT NEMO and by targeted renal PT NEMO inhibition with mesoscale nanoparticle–encapsulated NEMO binding peptide (NBP MNP). We subjected renal PT NEMO–deficient mice, WT mice, and C57BL/6 mice to sham surgery or 30 minutes of renal ischemia and reperfusion (IR). C57BL/6 mice received NBP MNP or empty MNP before renal IR injury. Mice treated with NBP MNP and mice deficient in renal PT NEMO were protected against ischemic AKI, having decreased renal tubular necrosis, inflammation, and apoptosis compared with control MNP-treated or WT mice, respectively. Recombinant peptidylarginine deiminase type 4 (rPAD4) targeted kidney PT NEMO to exacerbate ischemic AKI in that exogenous rPAD4 exacerbated renal IR injury in WT mice but not in renal PT NEMO–deficient mice. Furthermore, rPAD4 upregulated proinflammatory cytokine mRNA and NF-κB activation in freshly isolated renal proximal tubules from WT mice but not from PT NEMO–deficient mice. Taken together, our studies suggest that renal PT NEMO plays a critical role in ischemic AKI by promoting renal tubular inflammation, apoptosis, and necrosis.

Comments

This work was originally published in JCI Insight, available at https://doi.org/10.1172/jci. insight.139246.

This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.