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Inflammation primes the murine kidney for recovery by activating AZIN1 adenosine-to-inosine editing
Segewkal Hawaze Heruye, … , Pierre C. Dagher, Takashi Hato
Segewkal Hawaze Heruye, … , Pierre C. Dagher, Takashi Hato
Published July 2, 2024
Citation Information: J Clin Invest. 2024;134(17):e180117. https://doi.org/10.1172/JCI180117.
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Research Article Nephrology

Inflammation primes the murine kidney for recovery by activating AZIN1 adenosine-to-inosine editing

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Abstract

The progression of kidney disease varies among individuals, but a general methodology to quantify disease timelines is lacking. Particularly challenging is the task of determining the potential for recovery from acute kidney injury following various insults. Here, we report that quantitation of post-transcriptional adenosine-to-inosine (A-to-I) RNA editing offers a distinct genome-wide signature, enabling the delineation of disease trajectories in the kidney. A well-defined murine model of endotoxemia permitted the identification of the origin and extent of A-to-I editing, along with temporally discrete signatures of double-stranded RNA stress and adenosine deaminase isoform switching. We found that A-to-I editing of antizyme inhibitor 1 (AZIN1), a positive regulator of polyamine biosynthesis, serves as a particularly useful temporal landmark during endotoxemia. Our data indicate that AZIN1 A-to-I editing, triggered by preceding inflammation, primes the kidney and activates endogenous recovery mechanisms. By comparing genetically modified human cell lines and mice locked in either A-to-I–edited or uneditable states, we uncovered that AZIN1 A-to-I editing not only enhances polyamine biosynthesis but also engages glycolysis and nicotinamide biosynthesis to drive the recovery phenotype. Our findings implicate that quantifying AZIN1 A-to-I editing could potentially identify individuals who have transitioned to an endogenous recovery phase. This phase would reflect their past inflammation and indicate their potential for future recovery.

Authors

Segewkal Hawaze Heruye, Jered Myslinski, Chao Zeng, Amy Zollman, Shinichi Makino, Azuma Nanamatsu, Quoseena Mir, Sarath Chandra Janga, Emma H. Doud, Michael T. Eadon, Bernhard Maier, Michiaki Hamada, Tuan M. Tran, Pierre C. Dagher, Takashi Hato

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Figure 4

Azin1 A-to-I–locked mice exhibit faster tissue recovery following ischemic injury compared with uneditable mice.

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Azin1 A-to-I–locked mice exhibit faster tissue recovery following ischem...
(A) Sanger sequencing chromatograms for wild-type (top), Azin1 A-to-I–uneditable (middle), and Azin1 A-to-I–locked homozygous mice (bottom). The CRISPR knockin strategy is depicted in Supplemental Figure 6A. (B) Serum creatinine levels 24 and 72 hours after a 20-minute bilateral IRI. (C) Kidney tissue Havcr1/kidney injury marker-1 (KIM1) levels as determined by RNA-Seq (counts per million). (D) Polyribosome profiling of kidneys from Azin1 A-to-I–locked and uneditable mice 24 hours after IRI. Two representative biological replicates are shown for each genotype. Mean polysome/monosome ratios for A-to-I–locked and uneditable genotypes are 3.3 and 2.8, respectively. (E) Hematoxylin and eosin staining 72 hours after IRI. Original magnification, ×40. (F) Western blotting for hypusine in the kidney after IRI.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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