2. Academic Validation
  3. Aurantiamide mitigates acute kidney injury by suppressing renal necroptosis and inflammation via GRPR-dependent mechanism

Aurantiamide mitigates acute kidney injury by suppressing renal necroptosis and inflammation via GRPR-dependent mechanism

  • Int Immunopharmacol. 2024 Sep 30:139:112745. doi: 10.1016/j.intimp.2024.112745.
Ruo-Bing He 1,  Wei Li 1,  Rui Yao 2,  Meng-Ying Xu 1,  Wei Dong 3,  Ying Chen 1,  Wei-Jian Ni 4,  Shuai-Shuai Xie 1,  Zheng-Hao Sun 5,  Chao Li 1,  Dong Liu 1,  Shuang-Jian Li 1,  Ming-Lu Ji 1,  Ya-Xin Ru 1,  Tian Zhao 1,  Qi Zhu 1,  Jia-Gen Wen 1,  Jun Li 1,  Juan Jin 6,  Ri-Sheng Yao 7,  Xiao-Ming Meng 8
Affiliations

Affiliations

  • 1 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
  • 2 Department of Urology, the First Affiliated Hospital of Anhui Medical University, Institute of Urology, Anhui Medical University, Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Hefei 230022, China.
  • 3 Department of Pediatrics, Second Clinical School of Medicine, Anhui Medical University, Hefei, China.
  • 4 Department of Pharmacy, Centre for Leading Medicine and Advanced Technologies of IHM, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Precision Pharmaceutical Preparations and Clinical Pharmacy, Hefei, Anhui, 230001, China.
  • 5 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; School of Basic Medicine, Anhui Medical University, Hefei 230032, China.
  • 6 Department of Pharmacology, School of Basic Medical Sciences, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei 230032, China. Electronic address: jinjuan@ahmu.edu.cn.
  • 7 School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China. Electronic address: rishengyao@163.com.
  • 8 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address: mengxiaoming@ahmu.edu.cn.
PMID: 39059099 DOI: 10.1016/j.intimp.2024.112745
Abstract

Acute kidney injury (AKI) manifests as a clinical syndrome characterised by the rapid accumulation of metabolic wastes, such as blood creatinine and urea nitrogen, leading to a sudden decline in renal function. Currently, there is a lack of specific therapeutic drugs for AKI. Previously, we identified gastrin-releasing peptide receptor (GRPR) as a pathogenic factor in AKI. In this study, we investigated the therapeutic potential of a novel Chinese medicine monomer, aurantiamide (AA), which exhibits structural similarities to our previously reported GRPR antagonist, RH-1402. We compared the therapeutic efficacy of AA with RH-1402 both in vitro and in vivo using various AKI models. Our results demonstrated that, in vitro, AA attenuated injury, Necroptosis, and inflammatory responses in human renal tubular epithelial cells subjected to repeated hypoxia/reoxygenation and lipopolysaccharide stimulation. In vivo, AA ameliorated renal tubular injury and inflammation in mouse models of ischemia/reperfusion and cecum ligation puncture-induced AKI, surpassing the efficacy of RH-1402. Furthermore, molecular docking and cellular thermal shift assay confirmed GRPR as a direct target of AA, which was further validated in primary cells. Notably, in GRPR-silenced HK-2 cells and GRPR systemic knockout mice, AA failed to mitigate renal inflammation and injury, underscoring the importance of GRPR in AA's mechanism of action. In conclusion, our study has demonstrated that AA serve as a novel antagonist of GRPR and a promising clinical candidate for AKI treatment.

Keywords

Acute kidney injury; Aurantiamide; GRPR; Inflammation; Necroptosis.

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