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Histone deacetylase-mediated silencing of PSTPIP2 expression contributes to AAI-induced PANoptosis
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  • Xu Chuanting,
  • Wang Qi,
  • Changlin Du,
  • Jiahui Dong,
  • Zhenming Zhang,
  • Na Cai,
  • Jun Li,
  • Cheng Huang,
  • Taotao Ma
Xu Chuanting
Anhui Medical University
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Wang Qi
Anhui Medical University
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Changlin Du
Anhui Medical University
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Jiahui Dong
Anhui Medical University
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Zhenming Zhang
Anhui Medical University
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Na Cai
Anhui Medical University
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Jun Li
Anhui Medical University
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Cheng Huang
Anhui Medical University

Corresponding Author:[email protected]

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Taotao Ma
Anhui Medical University
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Abstract

Background and Purpose: Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by using herbal medicines. Currently, no therapies are available to treat or prevent AAN. Histone deacetylase (HDAC) plays a crucial role in the development and progression of renal disease. We tested whether HDAC inhibitors could prevent AAN and determined the underlying mechanism. Experimental Approach: HDACs expression in the kidneys was examined. Mouse kidney and renal tubular epithelial cell damage were assessed after exposure to HDAC1 and HDAC2 blockade (FK-228). Conditional knock-in of Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) in the kidney and knockdown of PSTPIP2 expression in PSTPIP2-knockin mice, pathological parameters, and kidney injuries were assessed. Key Results: Aristolochic acid upregulated the expression of HDAC1 and HDAC2 in the kidneys. Notably, the HDAC1 and -2 specific inhibitor, romidepsin (FK228, Depsipeptide), suppressed aristolochic acid-induced kidney injury, epithelial cell pyroptosis, apoptosis, and necroptosis (PANoptosis). Moreover, romidepsin upregulated PSTPIP2 in renal tubular epithelial cells, which was enhanced by aristolochic acid treatment. Conditional knock-in of PSTPIP2 in the kidney protected against AAN. In contrast, the knockdown of PSTPIP2 expression in PSTPIP2-knockin mice restored kidney damage and PANoptosis. PSTPIP2 function was determined in vitro using PSTPIP2 knockdown or overexpression in mTEC. Additionally, PSTPIP2 was found to regulate Caspase-8 in Aristolochic acid nephropathy. Conclusion and Implications: HDAC-mediated silencing of PSTPIP2 may contribute to aristolochic acid nephropathy. Hence, HDAC1 and -2 specific inhibitors or PSTPIP2 could be valuable therapeutic agents for the prevention of aristolochic acid nephropathy.
16 Feb 2023Submitted to British Journal of Pharmacology
17 Feb 2023Submission Checks Completed
17 Feb 2023Assigned to Editor
17 Feb 2023Review(s) Completed, Editorial Evaluation Pending
05 Mar 2023Reviewer(s) Assigned
04 May 2023Editorial Decision: Revise Minor
27 Jul 20231st Revision Received
28 Jul 2023Submission Checks Completed
28 Jul 2023Review(s) Completed, Editorial Evaluation Pending
28 Jul 2023Assigned to Editor
13 Aug 2023Reviewer(s) Assigned
16 Oct 2023Editorial Decision: Revise Minor
21 Nov 20232nd Revision Received
22 Nov 2023Submission Checks Completed
22 Nov 2023Assigned to Editor
22 Nov 2023Review(s) Completed, Editorial Evaluation Pending