Auto- and paracrine rewiring of NIX-mediated mitophagy by insulin-like growth factor-binding protein 7 in septic AKI escalates inflammation-coupling tubular damage

  • Life Sci. 2023 Apr 1;121653. doi: 10.1016/j.lfs.2023.121653.
Bang-Chuan Hu  1 ,  Jing-Wen Zhu  1 ,  Guo-Hua Wu  2 ,  Juan-Juan Cai  3 ,  Xue Yang  4 ,  Zi-Qiang Shao  1 ,  Yang Zheng  1 ,  Jun-Mei Lai  5 ,  Ye Shen  5 ,  Xiang-Hong Yang  1 ,  Jing-Quan Liu  1 ,  Ren-Hua Sun  1 ,  Hai-Ping Zhu  6 ,  Xiang-Ming Ye  5 ,  Shi-Jing Mo  7
Affiliations
  • 1. Emergency and Intensive Care Unit Center, Intensive Care Unit, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, Zhejiang, PR China.
  • 2. Zhejiang University, School of Medicine, Zhejiang University, Hangzhou 310029, Zhejiang, PR China.
  • 3. Department of Pathology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, Zhejiang, PR China.
  • 4. Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, Zhejiang, PR China.
  • 5. Center for Rehabilitation Medicine, Department of Intensive Rehabilitation Care Unit, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, Zhejiang, PR China; Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, Zhejiang, PR China.
  • 6. Department of Intensive Care Unit, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
  • 7. Center for Rehabilitation Medicine, Department of Intensive Rehabilitation Care Unit, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, Zhejiang, PR China; Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, Zhejiang, PR China; Emergency and Intensive Care Unit Center, Intensive Care Unit, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, Zhejiang, PR China. Electronic address: [email protected].
PMID: 37011875 DOI: 10.1016/j.lfs.2023.121653
Abstract

Aims: Inflammation-coupling tubular damage (ICTD) contributes to pathogenesis of septic acute kidney injury (AKI), in which insulin-like growth factor-binding protein 7 (IGFBP-7) serves as a biomarker for risk stratification. The current study aims to discern how IGFBP-7 signalling influences ICTD, the mechanisms that underlie this process and whether blockade of the IGFBP-7-dependent ICTD might have therapeutic value for septic AKI.

Materials and methods: In vivo characterization was carried out in B6/JGpt-Igfbp7em1Cd1165/Gpt mice subjected to cecal ligation and puncture (CLP). Transmission electron microscopy, immunofluorescence, flow cytometry, immunoblotting, ELISA, RT-qPCR and dual-luciferase reporter assays were used to determine mitochondrial functions, cell Apoptosis, cytokine secretion and gene transcription.

Key findings: ICTD augments the transcriptional activity and protein secretion of tubular IGFBP-7, which enables an auto- and paracrine signalling via deactivation of IGF-1 receptor (IGF-1R). Genetic knockout (KO) of IGFBP-7 provides renal protection, improves survival and resolves inflammation in murine models of cecal ligation and puncture (CLP), while administering recombinant IGFBP-7 aggravates ICTD and inflammatory invasion. IGFBP-7 perpetuates ICTD in a NIX/BNIP3-indispensable fashion through dampening Mitophagy that restricts redox robustness and preserves mitochondrial clearance programs. Adeno-associated viral vector 9 (AAV9)-NIX short hairpin RNA (shRNA) delivery ameliorates the anti-septic AKI phenotypes of IGFBP-7 KO. Activation of BNIP3-mediated Mitophagy by mitochonic acid-5 (MA-5) effectively attenuates the IGFBP-7-dependent ICTD and septic AKI in CLP mice.

Significance: Our findings identify IGFBP-7 is an auto- and paracrine manipulator of NIX-mediated Mitophagy for ICTD escalation and propose that targeting the IGFBP-7-dependent ICTD represents a novel therapeutic strategy against septic AKI.

Keywords
Inflammation-coupling tubular damage; Insulin-like growth factor-binding protein 7; Mitophagy; Septic acute kidney injury.
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