tetano
Editor, Senior Moderator
Cell Death Discov
. 2023 Aug 10;9(1):293.
doi: 10.1038/s41420-023-01584-x. Inhibition of Toll-like receptor 4 and Interleukin-1 receptor prevent SARS-CoV-2 mediated kidney injury
Daigo Nakazawa[SUP] #[/SUP][SUP] 1 [/SUP], Yohei Takeda[SUP] #[/SUP][SUP] 2 3 [/SUP], Masatoshi Kanda[SUP] #[/SUP][SUP] 4 [/SUP], Utano Tomaru[SUP] 5 [/SUP], Haruko Ogawa[SUP] 3 [/SUP], Takashi Kudo[SUP] 6 [/SUP], Satoka Shiratori-Aso[SUP] 6 [/SUP], Kanako Watanabe-Kusunoki[SUP] 6 [/SUP], Yusho Ueda[SUP] 6 [/SUP], Atsuko Miyoshi[SUP] 6 [/SUP], Fumihiko Hattanda[SUP] 6 [/SUP], Saori Nishio[SUP] 6 [/SUP], Ryo Uozumi[SUP] 7 [/SUP], Akihiro Ishizu[SUP] 8 [/SUP], Tatsuya Atsumi[SUP] 6 [/SUP]
Affiliations
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.
. 2023 Aug 10;9(1):293.
doi: 10.1038/s41420-023-01584-x. Inhibition of Toll-like receptor 4 and Interleukin-1 receptor prevent SARS-CoV-2 mediated kidney injury
Daigo Nakazawa[SUP] #[/SUP][SUP] 1 [/SUP], Yohei Takeda[SUP] #[/SUP][SUP] 2 3 [/SUP], Masatoshi Kanda[SUP] #[/SUP][SUP] 4 [/SUP], Utano Tomaru[SUP] 5 [/SUP], Haruko Ogawa[SUP] 3 [/SUP], Takashi Kudo[SUP] 6 [/SUP], Satoka Shiratori-Aso[SUP] 6 [/SUP], Kanako Watanabe-Kusunoki[SUP] 6 [/SUP], Yusho Ueda[SUP] 6 [/SUP], Atsuko Miyoshi[SUP] 6 [/SUP], Fumihiko Hattanda[SUP] 6 [/SUP], Saori Nishio[SUP] 6 [/SUP], Ryo Uozumi[SUP] 7 [/SUP], Akihiro Ishizu[SUP] 8 [/SUP], Tatsuya Atsumi[SUP] 6 [/SUP]
Affiliations
- PMID: 37563112
- 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.