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ALKBH5 抑制通过促进 Ccl28 m6A 修饰和增加 Treg 募集来减轻雄性小鼠的 I/R 诱导的肾损伤。

Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment.

机构信息

Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.

Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.

出版信息

Nat Commun. 2023 Mar 1;14(1):1161. doi: 10.1038/s41467-023-36747-y.

DOI:10.1038/s41467-023-36747-y
PMID:36859428
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9977869/
Abstract

Ischemia reperfusion injury (IRI) is a common cause of acute kidney injury (AKI). The role of Nmethyladenosine (m6A) modification in AKI remains unclear. Here, we characterize the role of AlkB homolog 5 (ALKBH5) and m6A modification in an I/R-induced renal injury model in male mice. Alkbh5-knockout mice exhibit milder pathological damage and better renal function than wild-type mice post-IRI, whereas Alkbh5-knockin mice show contrary results. Also conditional knockout of Alkbh5 in the tubular epithelial cells alleviates I/R-induced AKI and fibrosis. CCL28 is identified as a target of ALKBH5. Furthermore, Ccl28 mRNA stability increases with Alkbh5 deficiency, mediating by the binding of insulin-like growth factor 2 binding protein 2. Treg recruitment is upregulated and inflammatory cells are inhibited by the increased CCL28 level in IRI-Alkbh5Ksp mice. The ALKBH5 inhibitor IOX1 exhibits protective effects against I/R-induced AKI. In summary, inhibition of ALKBH5 promotes the m6A modifications of Ccl28 mRNA, enhancing its stability, and regulating the Treg/inflammatory cell axis. ALKBH5 and this axis is a potential AKI treatment target.

摘要

缺血再灌注损伤（IRI）是急性肾损伤（AKI）的常见原因。N6-甲基腺苷（m6A）修饰在 AKI 中的作用尚不清楚。在这里，我们描述了 AlkB 同源物 5（ALKBH5）和 m6A 修饰在雄性小鼠 I/R 诱导的肾损伤模型中的作用。Alkbh5 基因敲除小鼠在 IRI 后表现出较轻的病理损伤和更好的肾功能，而 Alkbh5 基因敲入小鼠则表现出相反的结果。此外，在肾小管上皮细胞中条件性敲除 Alkbh5 可减轻 I/R 诱导的 AKI 和纤维化。CCL28 被鉴定为 ALKBH5 的靶标。此外，CCL28 mRNA 稳定性随着 Alkbh5 的缺乏而增加，由胰岛素样生长因子 2 结合蛋白 2 的结合介导。在 IRI-Alkbh5Ksp 小鼠中，CCL28 水平的增加上调了 Treg 募集并抑制了炎症细胞。ALKBH5 抑制剂 IOX1 对 I/R 诱导的 AKI 具有保护作用。总之，抑制 ALKBH5 可促进 Ccl28 mRNA 的 m6A 修饰，增强其稳定性，并调节 Treg/炎症细胞轴。ALKBH5 和该轴是潜在的 AKI 治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/707373cfd774/41467_2023_36747_Fig9_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/c128ec63d2ba/41467_2023_36747_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/decb0426fe01/41467_2023_36747_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/2d717db04428/41467_2023_36747_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/0d0fbce535a9/41467_2023_36747_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/707373cfd774/41467_2023_36747_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/e5a76099abfe/41467_2023_36747_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/5de04420b7dc/41467_2023_36747_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/42b52350cd60/41467_2023_36747_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/041b79f16807/41467_2023_36747_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/c128ec63d2ba/41467_2023_36747_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/decb0426fe01/41467_2023_36747_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/2d717db04428/41467_2023_36747_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/0d0fbce535a9/41467_2023_36747_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e187/9977869/707373cfd774/41467_2023_36747_Fig9_HTML.jpg

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