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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.

SUBMITTER: Wang W

PROVIDER: S-EPMC8787402 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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

Wang Wenbiao W Chen Junzhe J Hu Dingwen D Pan Pan P Liang Liying L Wu Wenjing W Tang Ying Y Huang Xiao R XR Yu Xueqing X Wu Jianguo J Lan Hui Y HY

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20211123 3

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 wor ...[more]

PMID: 34813685

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Project description:UnlabelledMany viruses replicate most efficiently in specific phases of the cell cycle, establishing or exploiting favorable conditions for viral replication, although little is known about the relationship between caliciviruses and the cell cycle. Microarray and Western blot analysis of murine norovirus 1 (MNV-1)-infected cells showed changes in cyclin transcript and protein levels indicative of a G1 phase arrest. Cell cycle analysis confirmed that MNV-1 infection caused a prolonging of the G1 phase and an accumulation of cells in the G0/G1 phase. The accumulation in G0/G1 phase was caused by a reduction in cell cycle progression through the G1/S restriction point, with MNV-1-infected cells released from a G1 arrest showing reduced cell cycle progression compared to mock-infected cells. MNV-1 replication was compared in populations of cells synchronized into specific cell cycle phases and in asynchronously growing cells. Cells actively progressing through the G1 phase had a 2-fold or higher increase in virus progeny and capsid protein expression over cells in other phases of the cell cycle or in unsynchronized populations. These findings suggest that MNV-1 infection leads to prolonging of the G1 phase and a reduction in S phase entry in host cells, establishing favorable conditions for viral protein production and viral replication. There is limited information on the interactions between noroviruses and the cell cycle, and this observation of increased replication in the G1 phase may be representative of other members of the Caliciviridae.ImportanceNoroviruses have proven recalcitrant to growth in cell culture, limiting our understanding of the interaction between these viruses and the infected cell. In this study, we used the cell-culturable MNV-1 to show that infection of murine macrophages affects the G1/S cell cycle phase transition, leading to an arrest in cell cycle progression and an accumulation of cells in the G0/G1 phase. Furthermore, we show that MNV replication is enhanced in the G1 phase compared to other stages of the cell cycle. Manipulating the cell cycle or adapting to cell cycle responses of the host cell is a mechanism to enhance virus replication. To the best of our knowledge, this is the first report of a norovirus interacting with the host cell cycle and exploiting the favorable conditions of the G0/G1 phase for RNA virus replication.

Project description:Acute kidney injury (AKI) is a common complication following transcatheter aortic valve implantation (TAVI) leading to increased mortality and morbidity. Urinary G1 cell cycle arrest proteins TIMP-2 and IGFBP7 have recently been suggested as sensitive biomarkers for early detection of AKI in critically ill patients. However, the precise role of urinary TIMP-2 and IGFBP7 in patients undergoing TAVI is unknown.In a prospective observational trial, 40 patients undergoing TAVI (either transaortic or transapical) were enrolled. Serial measurements of TIMP-2 and IGFBP7 were performed in the early post interventional course. The primary clinical endpoint was the occurrence of AKI stage 2/3 according to the KDIGO classification.Now we show, that ROC analyses of [TIMP-2]*[IGFBP7] on day one after TAVI reveals a sensitivity of 100 % and a specificity of 90 % for predicting AKI 2/3 (AUC 0.971, 95 % CI 0.914-1.0, SE 0.0299, p = 0.001, cut-off 1.03). In contrast, preoperative and postoperative serum creatinine levels as well as glomerular filtration rate (GFR) and perioperative change in GFR did not show any association with the development of AKI. Furthermore, [TIMP-2]*[IGFBP7] remained stable in patients with AKI ≤1, but its levels increased significantly as early as 24 h after TAVI in patients who developed AKI 2/3 in the further course (4.77 ± 3.21 vs. 0.48 ± 0.68, p = 0.022). Mean patients age was 81.2 ± 5.6 years, 16 patients were male (40.0 %). 35 patients underwent transapical and five patients transaortic TAVI. 15 patients (37.5 %) developed any kind of AKI; eight patients (20 %) met the primary endpoint and seven patients required renal replacement therapy (RRT) within 72 h after surgery.Early elevation of urinary cell cycle arrest biomarkers after TAVI is associated with the development of postoperative AKI. [TIMP-2]*[IGFBP7] provides an excellent diagnostic accuracy in the prediction of AKI that is superior to that of serum creatinine.

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

Publications

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

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