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

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

  • Cell Death Discov. 2023 Aug 10;9(1):293. doi: 10.1038/s41420-023-01584-x.
Daigo Nakazawa # 1,  Yohei Takeda # 2 3,  Masatoshi Kanda # 4,  Utano Tomaru 5,  Haruko Ogawa 3,  Takashi Kudo 6,  Satoka Shiratori-Aso 6,  Kanako Watanabe-Kusunoki 6,  Yusho Ueda 6,  Atsuko Miyoshi 6,  Fumihiko Hattanda 6,  Saori Nishio 6,  Ryo Uozumi 7,  Akihiro Ishizu 8,  Tatsuya Atsumi 6
Affiliations

Affiliations

  • 1 Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. daigo-na@med.hokudai.ac.jp.
  • 2 Research Center for Global Agromedicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan.
  • 3 Department of Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan.
  • 4 Department of Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan.
  • 5 Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
  • 6 Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
  • 7 Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Japan.
  • 8 Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.
  • # Contributed equally.
PMID: 37563112 DOI: 10.1038/s41420-023-01584-x
Abstract

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.

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