Mixed lineage kinase 3 mediates SARS‐CoV‐2‐induced kidney injury via the Hsp70‐IL‐17A axis

Abstract Although the COVID‐19 pandemic is now considered over, the virus remains prevalent, and regular, on‐time vaccination is recommended. Traditional and RNA‐based vaccines have proven lifesaving for millions worldwide; however, their long‐term efficacy remains unknown. The unmet need is to identify interventions that mitigate the severity of SARS‐CoV‐2 infection and associated health complications, including damage to multiple organs. Pro‐inflammatory cytokines, including tumor necrosis factor (TNF), play a crucial role in the pathogenesis of COVID‐19 and the progression to multiple organ failure. The present study describes the role of Mixed Lineage Kinase 3 (MLK3), a TNF downstream target and mitogen‐activated protein kinase upstream regulator, in SARS‐CoV‐2‐induced kidney injury. MLK3 activity was higher in SARS‐CoV‐2‐infected K18‐hACE2 mice and in human kidneys, and it positively correlated with kidney injury. MLK3 transcriptionally upregulated TMPRSS2 expression via the NFATc1, and genetic or pharmacological inhibition of MLK3 mitigated SARS‐CoV‐2 pseudovirus entry into kidney cells. SARS‐CoV‐2 spike glycoprotein receptor binding domain (Spike‐RBD) activated MLK3, thereby regulating IL‐17A. Heat shock protein 70 (Hsp70) interacts with MLK3 and regulates Spike‐RBD‐induced IL‐17A production and ultimately apoptosis in kidney cells. Our results suggest that MLK3 inhibitors could serve as a therapeutic intervention in COVID‐19 patients with acute kidney injury.