COVID-19 News: Insights Into The Mechanism Behind COVID-19-Induced Acute Kidney Injury And The Potential Therapeutic Role Of Quercetin

COVID-19 News: The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed significant challenges to healthcare systems worldwide. One of the complications associated with this novel virus is acute kidney injury (AKI), which has been observed in critically ill COVID-19 patients and is linked to high mortality rates. Patients with preexisting conditions such as hypertension, diabetes, and chronic kidney disease are particularly vulnerable to COVID-19-induced AKI. The underlying mechanisms of AKI in the context of COVID-19 have remained largely elusive.


 
In COVID-19, a phenomenon known as the "cytokine storm" is observed in critically ill patients. This cytokine storm is characterized by the excessive release of proinflammatory cytokines, such as interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α), and monocyte chemotactic protein-1 (MCP-1), resulting in systemic inflammation. Understanding the mechanisms underlying this cytokine storm and its relationship with AKI is crucial for the development of effective treatments for severe COVID-19 cases.
 
In this COVID-19 News report, we explore a recent study conducted by Chinese researchers from various institutions in China, including the Guangdong Cardiovascular Institute in China, which sheds light on the role of the SARS-CoV-2 N protein in inducing AKI via a mechanism involving the activation of M1 proinflammatory macrophages through Mincle-dependent signaling. Additionally, we delve into the potential therapeutic role of quercetin, a natural compound with antiviral, anti-inflammatory, and antioxidant properties, in mitigating COVID-19-associated AKI.
 
SARS-CoV-2 N Protein and Acute Kidney Injury
The study conducted by the research team sought to uncover the mechanisms underlying COVID-19-associated AKI. They utilized diabetic db/db mice and overexpressed the SARS-CoV-2 N protein in these mice to mimic the viral infection. The results were striking: the overexpression of the N protein led to a significant increase in tubular cell death and the release of high mobility group box 1 (HMGB1), a molecule known as a damage-associated molecular pattern (DAMP).
 
DAMPs are molecules released from damaged cells, and they play a key role in activating the immune response. In this case, the release of HMGB1 triggered the activation of M1 proinflammatory macrophages and the production of proinflammatory cytokines, including IL-6, TNF-α, and MCP-1. This activation occurred through a signaling pathway involving Mincle, Syk, and NF-κB.
 
The in vitro experiments conducted by the researchers further confirmed these findings. Overexpression of the SARS-CoV-2 N protein caused injured tubular cells to release HMGB1 under high advanced glycation end product (AGE) conditions, which resulted in the activation of M1 macrophages and the production of proinflammatory cytokines through the Mincle-Syk-NF-κB-dependent mechanism.
 
This study provides crucial insights into the role of the SARS-CoV-2 N protein in AKI. It demonstrates that SARS-CoV-2 N protein-induced AKI in diabetic mice is associated with the activation of M1 macrophages via the Mincle-dependent pathway, offering a potential explanation for the cytokine storm observed in severe COVID-19 cases.
 
Quercetin: A Potential Therapeutic Agent
Quercetin is a flavonoid compound found in various Chinese herbs and dietary supplements. It is known for its wide range of pharmacological effects, including antiviral, antioxidant, and anti-inflammatory properties. Clinical trials have shown that the oral administration of quercetin significantly improves the severity of COVID-19 symptoms. Molecular docking studies suggest that quercetin may inhibit SARS-CoV-2 proteases, thereby impeding viral infection.
 
The research team investigated the effects of quercetin on SARS-CoV-2 N protein-induced AKI in db/db mice. The results were promising, as quercetin treatment significantly ameliorated the AKI. Importantly, the study elucidated the mechanistic basis for this therapeutic effect.
 
Quercetin was found to inhibit the release of HMGB1, a critical DAMP, and inactivate M1 proinflammatory macrophages while promoting the development of reparative M2 macrophages. This was achieved by suppressing the Mincle-Syk-NF-κB signaling pathway both in vivo and in vitro.
 
In summary, quercetin's effectiveness in mitigating SARS-CoV-2 N protein-induced AKI was attributed to its ability to block the binding of HMGB1 to Mincle and inhibit M1 macrophage activation. This dual action not only decreased inflammation but also promoted tissue repair through M2 macrophage activation.
 
Clinical Implications
The findings from this study hold significant clinical relevance. They suggest that SARS-CoV-2 N protein can play a pathogenic role in AKI through the activation of M1 macrophages via the Mincle-dependent mechanism. Furthermore, the study highlights quercetin as a potential therapeutic agent for COVID-19-associated AKI.

By inhibiting M1 macrophage activation and promoting M2 macrophage responses, quercetin has the potential to reduce the severity of AKI in COVID-19 patients. This could be particularly beneficial for individuals with preexisting conditions, such as diabetes, who are at a higher risk of developing AKI during a COVID-19 infection.
 
The study's findings also shed light on the role of DAMPs, such as HMGB1, in inducing the cytokine storm observed in critically ill COVID-19 patients. This newfound understanding could pave the way for the development of targeted therapies to modulate DAMP-mediated inflammation.
 
Conclusion
The study conducted by the collaborative research team offers valuable insights into the pathogenesis of AKI in the context of COVID-19. The SARS-CoV-2 N protein's role in inducing AKI by activating M1 macrophages through the Mincle-dependent mechanism provides a clearer understanding of the underlying mechanisms.
 
Moreover, the study underscores the therapeutic potential of quercetin in mitigating COVID-19-associated AKI. By inhibiting M1 macrophage activation and promoting the shift towards M2 macrophages, quercetin may provide an effective means of reducing AKI severity in COVID-19 patients.
 
These findings contribute to the growing body of knowledge on COVID-19 and provide a foundation for further research into targeted therapies for AKI and the cytokine storm associated with severe cases of the disease. As the world continues to grapple with the challenges posed by the pandemic, a better understanding of the disease's pathophysiology and potential treatments is of paramount importance.
 
The study findings were published in the peer reviewed journal: Frontiers in Immunology.
https://www.frontiersin.org/articles/10.3389/fimmu.2023.1264447/full
 
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