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

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 1

AZIN1 A-to-I editing status in non-cancerous diseases in humans.

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AZIN1 A-to-I editing status in non-cancerous diseases in humans. (A) Dis...
(A) Distribution of AZIN1 A-to-I editing rates (percent of edited reads over total reads) in prospectively collected blood from male children aged 6–11 years, before and after Plasmodium falciparum malaria infection. Individuals were classified as early fever (symptomatic and first-time infection), delayed fever (asymptomatic and first-time infection, subsequently developing malarial symptoms), and immune (infected but never developing symptoms). (B) Representative read coverage near the AZIN1 editing site for one sample. Note that inosine is sequenced as guanosine. The human AZIN1 gene is encoded on the minus strand, hence the T-to-C mutation, not A-to-G, in the coverage track. Light-blue-colored reads (F2R1 paired-end orientation) indicate the proper directionality of reads mapped to the minus strand. (C) Distribution of AZIN1 A-to-I editing rates in kidney biopsies with a pathology diagnosis of diabetic kidney disease (DKD), acute kidney injury (AKI), or reference nephrectomy samples. Each column represents one sample. (D) Stacked bar chart summarizing total numbers of differentially expressed A-to-I editing sites genome-wide under the indicated conditions. For each comparison, editing sites are divided on the x axis based on the direction of fold change. For example, in the DKD versus reference comparison, approximately 20,000 sites are more edited in DKD, whereas approximately 10,000 sites are more edited in reference nephrectomy samples. (E) Heatmap displaying the top 500 differentially expressed A-to-I editing sites between diabetic nephropathy and reference nephrectomy samples. The differentially expressed sites are categorized based on repeat classes. (F) Comparison between AKI biopsies and reference nephrectomy samples.