Inhibition of Toll-like receptor 4 and Interleukin-1 receptor prevent SARS-CoV-2 mediated kidney injury

• Published in: Cell death discovery 2023-08, Vol.9 (1), p.293-293, Article 293
• Main Authors: Nakazawa, Daigo, Takeda, Yohei, Kanda, Masatoshi, Tomaru, Utano, Ogawa, Haruko, Kudo, Takashi, Shiratori-Aso, Satoka, Watanabe-Kusunoki, Kanako, Ueda, Yusho, Miyoshi, Atsuko, Hattanda, Fumihiko, Nishio, Saori, Uozumi, Ryo, Ishizu, Akihiro, Atsumi, Tatsuya
• Format: Article
• Language: English
• Subjects: 631/250/1933; 631/250/2499; 692/699/1585/4; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell death; Cell injury; Cell lines; Coronaviruses; COVID-19; Cytokines; Endothelial cells; Epithelial cells; Gene expression; Inflammation; Interleukin 1; Interleukin 1 receptors; Kidneys; Life Sciences; NF-κB protein; Pathophysiology; Severe acute respiratory syndrome coronavirus 2; Stem Cells; Therapeutic applications; Therapeutic targets; TLR4 protein; Toll-like receptors; Transcriptomics
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-023-01584-x

Acute kidney injury (AKI) is a common and severe complication of the coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly affects the glomerular and tubular epithelial cells to induce AKI; however, its pathophysiology remains unclear. Here, we explored the underlying mechanisms and therapeutic targets of renal involvement in COVID-19. We developed an in vitro human kidney cellular model, including immortalized tubular epithelial and endothelial cell lines, demonstrating that SARS-CoV-2 directly triggers cell death. To identify the molecular targets in the process of SARS-CoV-2-mediated cell injury, we performed transcriptional analysis using RNA sequencing. Tubular epithelial cells were more prone to dying by SARS-CoV-2 than endothelial cells; however, SARS-CoV-2 did not replicate in renal cells, distinct from VeroE6/transmembrane protease serine 2 cells. Transcriptomic analysis revealed increased inflammatory and immune-related gene expression levels in renal cells incubated with SARS-CoV-2. Toll-like receptor (TLR) 3 in renal cells recognized viral RNA and underwent cell death. Furthermore, analysis of upstream regulators identified several key transcriptional regulators. Among them, inhibition of the interleukin-1 receptor (IL-1R) and TLR4 pathways protects tubular epithelial and endothelial cells from injury via regulation of the signal transducer and activator of transcription protein-3/nuclear factor-kB pathway. Our results reveal that SARS-CoV-2 directly injures renal cells via the proinflammatory response without viral replication, and that IL-1R and TLR4 may be used as therapeutic targets for SARS-CoV-2 mediated kidney injury.