Gene signature and prediction model of the mitophagy-associated immune microenvironment in renal ischemia-reperfusion injury

Front Immunol. 2023 Mar 28:14:1117297. doi: 10.3389/fimmu.2023.1117297. eCollection 2023.

Abstract

Background: Renal ischemia-reperfusion injury (IRI) is an inevitable occurrence during kidney transplantation. Mitophagy, ferroptosis, and the associated immune microenvironment (IME) have been shown to play important roles in renal IRI. However, the role of mitophagy-associated IME genes in IRI remains unclear. In this study, we aimed to construct a prediction model of IRI prognosis based on mitophagy-associated IME genes.

Method: The specific biological characteristics of the mitophagy-associated IME gene signature were comprehensively analyzed using public databases such as GEO, Pathway Unification, and FerrDb. Correlations between the expression of prognostic genes and immune-related genes and IRI prognosis were determined by Cox regression, LASSO analysis, and Pearson's correlation. Molecular validation was performed using human kidney 2 (HK2) cells and culture supernatant as well as the serum and kidney tissues of mice after renal IRI. Gene expression was measured by PCR, and inflammatory cell infiltration was examined by ELISA and mass cytometry. Renal tissue damage was characterized using renal tissue homogenate and tissue sections.

Results: The expression of the mitophagy-associated IME gene signature was significantly correlated with IRI prognosis. Excessive mitophagy and extensive immune infiltration were the primary factors affecting IRI. In particular, FUNDC1, SQSTM1, UBB, UBC, KLF2, CDKN1A, and GDF15 were the key influencing factors. In addition, B cells, neutrophils, T cells, and M1 macrophages were the key immune cells present in the IME after IRI. A prediction model for IRI prognosis was constructed based on the key factors associated with the mitophagy IME. Validation experiments in cells and mice indicated that the prediction model was reliable and applicable.

Conclusion: We clarified the relationship between the mitophagy-related IME and IRI. The IRI prognostic prediction model based on the mitophagy-associated IME gene signature provides novel insights on the prognosis and treatment of renal IRI.

Keywords: gene signature; immune microenvironment; mitophagy; prediction model; renal ischemia-reperfusion injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Kidney / metabolism
  • Kidney Transplantation* / adverse effects
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondrial Proteins / metabolism
  • Mitophagy / genetics
  • Neutrophils / metabolism
  • Reperfusion Injury*

Substances

  • FUNDC1 protein, mouse
  • Membrane Proteins
  • Mitochondrial Proteins

Grants and funding

This work was supported by the Clinical Plus Excellence Program of Renji Hospital (NO. 2021ZYA022); Shanghai Shenkang Hospital Development Center, Clinical Skills and Clinical Innovation program (NO. SHDC2020CR5012); and the Clinical Scientific Research Innovation Cultivation Program, Renji Hospital, School of Medicine, Shanghai Jiao Tong University (NO. RJPY-D2X-010);The National Natural Science Fundation of China (NO. 82001951);The Key Research and Development Program of Jiangsu Province (BE2020654,BE2020655). A Special Supportive Program for Organ Transplantation by COTDF (NO.2019JYJH14).