Shenkang injection protects against renal fibrosis by reducing perforin expression through the STING/TBK1/IRF3 signaling pathways in natural killer cells

Junfeng Hao, Xin Huang, Jibin Guan, Jingwen Feng, Dongyang Li, Shiyu Cao, Yuxuan Li, Yong Liao, Xiaotian Sun, Dajun Liu, Xiaoyu Li

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9 Scopus citations

Abstract

BACKGROUND: Immune activation, chronic inflammation, and renal interstitial fibrosis (RIF) are associated with chronic kidney disease (CKD). The herbal formula, Shenkang injection (SKI), has been reported to attenuate RIF. However, the mechanisms by which SKI alleviates renal fibrosis, especially the role of natural killer (NK) cells, are unknown and require exploration.

PURPOSE: This study aimed to determine the mechanisms by which SKI alleviates RIF.

METHODS: Differential gene expression between CKD mice and control groups was explored using bioinformatics analysis. To reveal how SKI reduces RIF in CKD, a CKD mouse model was established using folic acid for in vivo studies, and human kidney-2 cells were used for in vitro experiments. The effects of various SKI doses were then determined. Immunohistochemical staining, Enzyme-linked immunosorbent assay, western blotting, and quantitative real-time PCR were used for pathological and molecular expression detection.

RESULTS: We first investigated the potential immune dysfunction in CKD using bioinformatics analysis. Some differentially expressed genes were enriched in immune-related functions. The expressions of perforin and interferon (IFN)-γ, which are mainly released by NK cells, were significantly higher in patients with CKD (p< 0.05). In vivo experiments showed that SKI alleviated renal fibrosis in a folic acid-induced renal fibrosis model. Serum creatinine and blood urea nitrogen levels were reduced in the high-dose SKI-treated group. Additionally, the mRNA and protein expression levels of type IV collagen and alpha-spinal muscular atrophy were reduced. Biochemical detection showed that SKI could also downregulate the activity of NK cells (by decreasing the expressions of perforin and IFN-γ). Increased levels of stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1)/IFN regulatory factor 3 (IRF3), phosphorylation of TBK1, and IRF3 in FA-induced RIF mice were alleviated by SKI treatment, which was consistent with the results of in vitro experiments.

CONCLUSION: These results demonstrated that SKI could decrease the activation of NK cells via the STING/TBK1/IRF3 signaling pathway, thereby alleviating RIF and protecting renal function in CKD. This may provide valuable evidence supporting the clinical use of SKI in the treatment of patients with CKD.

Original languageEnglish (US)
Article number154206
JournalPhytomedicine
Volume104
DOIs
StatePublished - Sep 2022

Bibliographical note

Funding Information:
We thank Editage for its linguistic assistance during the preparation of this manuscript. We are grateful for Shuke Ge from Emergency management department of Liaoning Center for Disease Control in data validation and Prevention and Xuefeng Zhang and Yajing Li from Nephrology Department of JinQiu Hospital Liaoning Province in manuscript editing. The graphic in Graphical abstract was created using BioRender (BioRender.com).

Publisher Copyright:
© 2022

Keywords

  • Chronic kidney disease
  • Interferon-γ
  • Natural killer cells
  • Perforin
  • Renal interstitial fibrosis
  • Shenkang injection
  • Folic Acid
  • Drugs, Chinese Herbal
  • Killer Cells, Natural
  • Signal Transduction
  • Humans
  • Renal Insufficiency, Chronic/drug therapy
  • Animals
  • Interferon Regulatory Factor-3/metabolism
  • Membrane Proteins/metabolism
  • Fibrosis
  • Protein Serine-Threonine Kinases
  • Mice
  • Interferons/metabolism
  • Perforin/metabolism

PubMed: MeSH publication types

  • Journal Article

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