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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 2

Azin1 A-to-I editing status in murine models of AKI.

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Azin1 A-to-I editing status in murine models of AKI.
(A) Bulk RNA-Seq an...
(A) Bulk RNA-Seq analysis on a murine model of endotoxemia (LPS). Gene set coregulation analysis showing sequential upregulation of pathways involved in NF-κB–mediated acute inflammation and in antiviral/interferon responses, followed by the integrated stress response, as indicated by enrichment of the Molecular Signatures Database Hallmark Gene Sets. Each dot corresponds to each animal. The colored lines in the background depict scaled expression of individual genes. ***Pairwise t test adjusted P < 0.05 compared with the preceding time point. (B) Principal component analysis showing overall gene expression changes over the course of endotoxemia in the kidney. (C) Serum creatinine levels at indicated time points after administration of LPS (4 mg/kg in C57BL/6J male mice). (D) Combined Ribo-Seq and RNA-Seq read coverage graphs for Azin1 after LPS challenge in the kidney. Reads are mapped to Ensembl transcript Azin1-201. Gray-colored reads represent RNA-Seq, whereas red/green/blue-colored reads represent codon frames for ribosome-protected fragments in Ribo-Seq. The top right panel confirms the translation of A-to-I–edited Azin1 (reanalysis of GEO GSE120877). (E) Percentage of Azin1 A-to-I editing under indicated conditions (based on stranded total RNA-Seq data). (F–H) Measurements of kidney tissue putrescine and spermidine levels by HPLC under indicated conditions. Representative HPLC chromatograms are also shown. For clarity, the traces are slightly shifted from each other on the x axis elution time. (I and J) Quantitation of RNA-Seq read counts (in counts per million) at the indicated time points. (K) Sanger sequencing showing timeline-specific Azin1 A-to-I editing observed in wild-type mouse kidneys after ischemia/reperfusion injury (IRI; arrowheads). (L) Measurements of kidney tissue spermidine levels by HPLC after IRI. *P < 0.05 vs. 0-hour control samples, 1-way ANOVA followed by Dunnett’s test for multiple treatment comparisons. 0** indicates kidney tissues harvested 20 minutes after ischemia without reperfusion.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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