Inflammatory stress in SARS-COV-2 associated Acute Kidney Injury

Abstract

Increasing clinical evidence shows that acute kidney injury (AKI) is a common and severe complication in critically ill COVID-19 patients. The older age, the severity of COVID-19 infection, the ethnicity, and the history of smoking, diabetes, hypertension, and cardiovascular disease are the risk factor for AKI in COVID-19 patients. Of them, inflammation may be a key player in the pathogenesis of AKI in patients with COVID-19. It is highly possible that SARS-COV-2 infection may trigger the activation of multiple inflammatory pathways including angiotensin II, cytokine storm such as interleukin-6 (IL-6), C-reactive protein (CRP), TGF-β signaling, complement activation, and lung-kidney crosstalk to cause AKI. Thus, treatments by targeting these inflammatory molecules and pathways with a monoclonal antibody against IL-6 (Tocilizumab), C3 inhibitor AMY-101, anti-C5 antibody, anti-TGF-β OT-101, and the use of CRRT in critically ill patients may represent as novel and specific therapies for AKI in COVID-19 patients.

Keywords: AKI; COVID-19; cytokines; inflammation; mechanisms.

Figure 1

Alterations of Ang II and Ang 1-7 signaling in COVID-19 associated AKI. SARS-COV-2 binds and downregulates ACE2, which may result in downregulation of Ang 1-7 while upregulating Ang II-AT signaling to promote AKI.

Figure 2

Possible mechanisms through which SARS-COV-2 may induce AKI by stimulating IL-6 signaling. SARS-COV-2 may activate IL-6-mIL-6/sIL6-JAK-STAT3 signaling, resulting in AKI, which can be blocked by Tocilizumab antibodies.

Figure 3

Possible role of CRP signaling in COVID-19-associated AKI. SARS-COV-2 infection may activate CRP signaling to cause AKI via TGF-β/Smad3-mediated G1 cell cycle arrest and NF-κB-dependent renal inflammation.

Figure 4

Proposed TGF-β signaling in COVID-19-associated AKI. SARS-COV-2 may induce G1 cell cycle arrest and cell death via TGF-β/Smad3-p21/p27 mechanism.