SARS-CoV-2 N protein induces hypokalemia in acute kidney injury mice via ENaC-dependent mechanism.

Hypokalemia is a prevalent complication of COVID-19 patients with acute kidney injury (AKI); however, mechanisms have yet to be fully understood. By single-nucleus RNA sequencing, we found that COVID-19 patients with AKI were associated with a marked upregulation of the epithelial sodium channel (ENaC) in the renal tubular epithelial cells (TECs). By using a mouse model of AKI induced by kidney-specific overexpressing SARS-CoV-2 N protein, we detected that overexpression of renal SARS-CoV-2 N protein could induce hypokalemia and AKI, which was associated with the upregulation of ENaC, ROMK, and BK proteins. Functionally, a patch-clamp study revealed that the overexpression of SARS-CoV-2 N protein largely increased the ENaC current in the TECs. Mechanically, we uncovered that kidney-specific overexpressing SARS-CoV-2 N protein could activate ENaC to cause hypokalemia and AKI directly by binding to the ENaCα and ENaCγ subunits and indirectly by activating the p38 MAPK pathway. Importantly, treatment with an ENaC specific inhibitor could protect against SARS-CoV-2 N-induced hypokalemia and AKI, revealing a regulatory role and therapeutic target of ENaC in SARS-CoV-2 N-induced hypokalemia and AKI. In conclusion, hypokalemia in COVID-19 AKI is induced by SARS-CoV-2 N protein via the ENaC-dependent mechanism. Targeting ENaC may offer a novel therapy for COVID-19 patients with AKI.