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An acute phase protein α₁-acid glycoprotein mitigates AKI and its progression to CKD through its anti-inflammatory action.

ABSTRACT: The molecular mechanism for acute kidney injury (AKI) and its progression to chronic kidney disease (CKD) continues to be unclear. In this study, we investigated the pathophysiological role of the acute phase protein α₁-acid glycoprotein (AGP) in AKI and its progression to CKD using AGP KO mice. Plasma AGP levels in WT mice were increased by about 3.5-fold on day 1-2 after renal ischemia-reperfusion (IR), and these values then gradually decreased to the level before renal IR on day 7-14. On day 1 after renal IR, the AGP KO showed higher renal dysfunction, tubular injury and renal inflammation as compared with WT. On day 14, renal function, tubular injury and renal inflammation in WT had recovered, but the recovery was delayed, and renal fibrosis continued to progress in AGP KO. These results obtained from AGP KO were rescued by the administration of human-derived AGP (hAGP) simultaneously with renal IR. In vitro experiments using RAW264.7 cells showed hAGP treatment suppressed the LPS-induced macrophage inflammatory response. These data suggest that endogenously induced AGP in early renal IR functions as a renoprotective molecule via its anti-inflammatory action. Thus, AGP represents a potential target molecule for therapeutic development in AKI and its progression CKD.

SUBMITTER: Watanabe H

PROVIDER: S-EPMC8041882 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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An acute phase protein α<sub>1</sub>-acid glycoprotein mitigates AKI and its progression to CKD through its anti-inflammatory action.

Watanabe Hiroshi H Fujimura Rui R Hiramoto Yuto Y Murata Ryota R Nishida Kento K Bi Jing J Imafuku Tadashi T Komori Hisakazu H Maeda Hitoshi H Mukunoki Ayumi A Takeo Toru T Nakagata Naomi N Tanaka Motoko M Matsushita Kazutaka K Fukagawa Masafumi M Maruyama Toru T

Scientific reports 20210412 1

The molecular mechanism for acute kidney injury (AKI) and its progression to chronic kidney disease (CKD) continues to be unclear. In this study, we investigated the pathophysiological role of the acute phase protein α<sub>1</sub>-acid glycoprotein (AGP) in AKI and its progression to CKD using AGP KO mice. Plasma AGP levels in WT mice were increased by about 3.5-fold on day 1-2 after renal ischemia-reperfusion (IR), and these values then gradually decreased to the level before renal IR on day 7- ...[more]

PMID: 33846468

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Project description:Acute kidney injury (AKI) progression to chronic kidney disease (CKD) represents a unique renal disease setting characterized by early renal cellular injury and regulated cell death, and later renal fibrosis, of which the critical role and nature of ferroptosis are only partially understood. Here, we report that renal tubular epithelial ferroptosis caused by HDAC3 (histone deacetylase 3) aberration and the resultant GPX4 suppression drives AKI-CKD progression. In mouse models of AKI-CKD transition induced by nephrotoxic aristolochic acid (AA) and folic acid (FA), renal tubular epithelial ferroptosis occurred early that coincided with preferential HDAC3 elevation and marked suppression of a core anti-ferroptosis enzyme GPX4 (glutathione peroxidase 4). Intriguingly, genetic Hdac3 knockout or administration of a HDAC3-selective inhibitor RGFP966 effectively mitigated the GPX4 suppression, ferroptosis and the fibrosis-associated renal functional loss. In cultured tubular epithelial cells, HDAC3 over-expression or inhibition inversely affected GPX4 abundances. Further analysis revealed that Gpx4 promoter contains a typical binding motif of transcription factor KLF5 (Kruppel-like factor 5). HDAC3 and KLF5 inducibly associated and bound to Gpx4 promoter upon AA treatment, leading to local histone hypoacetylation and GPX4 transactivation inhibition, which was blocked by RGFP966 and a KLF5 inhibitor ML264, respectively, suggesting that KLF5 co-regulated the HDAC3-incurred Gpx4 transcription inhibition. More importantly, in AKI-CKD mice receiving a GPX4 inactivator RSL3, the anti-ferroptosis and renoprotective effects of RGFP966 were largely abrogated, indicating that GPX4 is an essential downstream mediator of the HDAC3 aberration and renal ferroptosis during AKI-CKD transition. Together, our study identified a critical epigenetic pathway of ferroptosis during AKI-CKD transition and suggested that the strategies preserving GPX4 by HDAC3 inhibition are potentially effective to reduce renal ferroptosis and slow AKI-CKD progression.

Dataset Information

An acute phase protein α₁-acid glycoprotein mitigates AKI and its progression to CKD through its anti-inflammatory action.

Publications

An acute phase protein α<sub>1</sub>-acid glycoprotein mitigates AKI and its progression to CKD through its anti-inflammatory action.

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Dataset Information

An acute phase protein α1-acid glycoprotein mitigates AKI and its progression to CKD through its anti-inflammatory action.

Publications

An acute phase protein α<sub>1</sub>-acid glycoprotein mitigates AKI and its progression to CKD through its anti-inflammatory action.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

An acute phase protein α₁-acid glycoprotein mitigates AKI and its progression to CKD through its anti-inflammatory action.