SARS‐CoV‐2 N Protein Induces Acute Kidney Injury via Smad3‐Dependent G1 Cell Cycle Arrest Mechanism

Abstract

COVID‐19 is infected by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and can cause severe multiple organ injury and death. Kidney is one of major target organs of COVID‐19 and acute kidney injury (AKI) is common in critically ill COVID‐19 patients. However, mechanisms through which COVID‐19 causes AKI remain largely unknown and treatment remains unspecific and ineffective. Here, the authors report that normal kidney‐specifically overexpressing SARS‐CoV‐2 N develops AKI, which worsens in mice under ischemic condition. Mechanistically, it is uncovered that SARS‐CoV‐2 N‐induced AKI is Smad3‐dependent as SARS‐CoV‐2 N protein can interact with Smad3 and enhance TGF‐β/Smad3 signaling to cause tubular epithelial cell death and AKI via the G1 cell cycle arrest mechanism. This is further confirmed in Smad3 knockout mice and cells in which deletion of Smad3 protects against SARS‐CoV‐2 N protein‐induced cell death and AKI in vivo and in vitro. Most significantly, it is also found that targeting Smad3 with a Smad3 pharmacological inhibitor is able to inhibit SARS‐CoV‐2 N‐induced AKI. In conclusion, the authors identify that SARS‐CoV‐2 N protein is a key mediator for AKI and induces AKI via the Smad3‐dependent G1 cell cycle arrest mechanism. Targeting Smad3 may represent as a novel therapy for COVID‐19‐asscoaited AKI.

Metabolic dyshomeostasis induced by SARS-CoV-2 structural proteins reveals immunological insights into viral olfactory interactions

“…As shown in Figure 9 , common hubs were predicted for each SARS-CoV-2 structural protein such as TGFB1/B3, SMAD and TEAD proteins, EGF, SPP1 and EDN1. It has been previously observed that SARS-CoV-2 N protein interacts with SMAD proteins enhancing TGF-beta signaling (Wang et al, 2022) whereas SARS-CoV-2 S protein triggers a transcriptional response associated to TGF-beta signaling (Biering et al, 2021). Interestingly, a therapeutic strategy focused on the inactivation of TGF-beta using integrin inhibitors has been proposed to mitigate COVID-19 severity (Huntington et al, 2022).…”

Smad3 Signatures in Renal Inflammation and Fibrosis

“…AKI is also a common clinical feature in critically ill patients with COVID-19, particularly in those with inflammatory stress and underlying disease conditions 78 . Strikingly, our most recent study discovered that among SARS-CoV-2 proteins, SARS-CoV-2 N protein is pathogenic for AKI as kidney-specifically overexpressing SARS-CoV-2 N protein can directly induce AKI and promote severe AKI under ischemic conditions 79 . Mechanically, we uncover that SARS-CoV-2 N protein can bind and activate Smad3 signaling to trigger the p21-dependent cell death pathway via the G1 cell cycle arrest mechanism 79 , 80 .…”

“…Strikingly, our most recent study discovered that among SARS-CoV-2 proteins, SARS-CoV-2 N protein is pathogenic for AKI as kidney-specifically overexpressing SARS-CoV-2 N protein can directly induce AKI and promote severe AKI under ischemic conditions 79 . Mechanically, we uncover that SARS-CoV-2 N protein can bind and activate Smad3 signaling to trigger the p21-dependent cell death pathway via the G1 cell cycle arrest mechanism 79 , 80 . Thus, targeting Smad3 by genic deletion of Smad3 or pharmacological inhibition of Smad3 signaling can protect against SARS-CoV-2 N-induced AKI 79 .…”

“…Mechanically, we uncover that SARS-CoV-2 N protein can bind and activate Smad3 signaling to trigger the p21-dependent cell death pathway via the G1 cell cycle arrest mechanism 79 , 80 . Thus, targeting Smad3 by genic deletion of Smad3 or pharmacological inhibition of Smad3 signaling can protect against SARS-CoV-2 N-induced AKI 79 . As Smad3 is a key mediator of renal fibrosis 51 , it is highly possible that after SARS-CoV-2 infection, intracellular release of SARS-CoV-2 N protein can bind and activate TGF-β/Smad3 signaling to induce the cell death pathway to trigger renal inflammation and “cytokine storm”, resulting in AKI.…”

Editorial: Immune Landscape of Kidney Pathology

“…Its failure is an important cause of patient death. In addition, kidney disease is a major contributor to patient death in a wide range of diseases such as diabetes, cancer, bacterial and viral infections (including COVID-19; Tang et al, 2021a ; Wang et al, 2021 ); leading to more than 6 million deaths worldwide each year. Thus, developing a better understanding, and treatment of, kidney disease is critical.…”