Targeting TLR-4 Signaling to Treat COVID-19-induced Acute Kidney Injury

Abstract

The newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has turned into a potentially fatal pandemic illness. Numerous acute kidney injury (AKI) cases have been reported, although diffuse alveolar destruction and acute respiratory failure are the major symptoms of SARS-CoV-2 infection. The AKI, often known as a sudden loss of kidney function, carries a greater risk of mortality and morbidity. AKI was the second most frequent cause of death after acute respiratory distress syndrome (ARDS) in critically ill patients with coronavirus disease 2019 (COVID-19). While most patients with COVID-19 have moderate symptoms, some have severe symptoms, such as septic shock and ARDS. Also, it has been proven that some patients have severe symptoms, such as the failure of several organs. The kidneys are often affected either directly or indirectly. The major signs of kidney involvement are proteinuria and AKI. It is hypothesized that multiple mechanisms contribute to kidney injury in COVID-19. Direct infection of podocytes and proximal tubular cells in the kidneys may lead to acute tubular necrosis and collapsing glomerulopathy. SARS-CoV2 may also trigger a cascade of immunological responses that lead to AKI, including cytokine storm (CS), macrophage activation syndrome, and Toll-like receptor type-4 activation (TLR-4). Other proposed processes of AKI include interactions between organs, endothelial failure, hypercoagulability, rhabdomyolysis, and sepsis. Furthermore, ischemic damage to the kidney might result from the decreased oxygen supply. This article focuses on kidney injury’s epidemiology, etiology, and pathophysiological processes. Specifically, it focuses on the CS and the role of TLR-4 in this process. To effectively manage and treat acute kidney damage and AKI in COVID-19, it is crucial to understand the underlying molecular pathways and pathophysiology.

Potential Alternative Receptors for SARS-CoV-2-Induced Kidney Damage: TLR-4, KIM-1/TIM-1, and CD147

“…Recent evidence has suggested that the binding of TLR4 to the SARS-CoV-2 spike protein could serve as an alternative gateway into human cells, ultimately, aggravating the hyperinflammatory response characterized by increased TNF- α , interleukin (IL)-1, IL-2, IL-6, IL-7, IL-18, interferon-gamma, granulocyte-macrophages colony-stimulating factor, and monocyte chemoattractant protein-levels, known as a cytokine storm, a hallmark feature of COVID-19 ( Fig. 1 ) [ 62 ]. In that regard, it has been documented that TLR4 has a stronger protein–protein interaction with SARS-CoV-2 compared to ACE2, with binding energy values of –120.2 and –29.2, respectively (the more negative, the stronger the binding) [ 63 ], a critical observation that requires further investigation.…”