Renal consequences of the novel coronavirus disease 2019 (COVID-19) and hydrogen sulfide as a potential therapy

Abstract

The novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a global pandemic which is primarily considered a respiratory illness. However, emerging reports show that the virus exhibits both pulmonary and extra-pulmonary manifestations in humans, with the kidney as a major extra-pulmonary target due to its abundant expression of angiotensin-converting enzyme 2 and transmembrane protease serine 2, which facilitate entry of the virus into cells. Acute kidney injury has become prevalent in COVID-19 patients without prior any history of kidney dysfunction. In addition, the virus also worsens kidney conditions and increases mortality of COVID-19 patients with pre-existing chronic kidney disease, renal cancer, diabetic nephropathy, end-stage kidney disease as well as dialysis and kidney transplant patients. In the search for antiviral agents for the treatment of COVID-19, hydrogen sulfide (H₂S), the third established member of gasotransmitter family, is emerging as a potential candidate, possessing important therapeutic properties including antiviral, anti-inflammatory, anti-thrombotic and antioxidant properties. A recent clinical study revealed higher serum H₂S levels in survivors of COVID-19 pneumonia with reduced interleukin-6 levels compared to fatal cases. In this review, we summarize the global impact of COVID-19 on kidney conditions and discuss the emerging role of H₂S as a potential COVID-19 therapy.

Keywords: Angiotensin-converting enzyme 2 (ACE2); Coronavirus disease 2019 (COVID-19); H(2)S donors; Hydrogen sulfide (H(2)S); Kidney; SARS-CoV-2.

Fig. 1

A diagram showing the attachment of SARS-CoV-2 to the ACE2 receptors expressed on the surface of proximal tubule epithelial cells. Invasion of the kidneys by SARS-CoV-2 leads to proteinuria, hematuria, abnormal kidney function parameters (urea, creatinine, uric acid and albumin), and occlusion of renal arteries and veins as well as collapsing glomerulopathy as a result of local cytokine storm syndrome.

Fig. 2

Possible mechanism of action of H₂S against SARS-CoV-2. Administration of H₂S donors may increase endogenous production of H₂S by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), 3-mecaptopyruvate sulfurtransferase (3-MST) and d-amino acid oxidase (DAO) and may also activate non-enzymatic pathway. H₂S interacts with angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 (not shown) and may block the binding of SARS-CoV-2 to these host cell proteins, thereby inhibiting entry of the virus into the host cell. H₂S may also alter SARS-CoV-2 membrane and inhibits its gene transcription including inhibiting the activation of nuclear factor-kappaB (NF-κB). In addition, H₂S may activate antioxidant pathway, leading to increased levels of antioxidant enzymes such as glutathione (GSH), nuclear factor-erythroid factor 2-related factor 2 (Nrf2) and superoxide dismutase (SOD), and suppressing overproduction of reactive oxygen species (ROS). Furthermore, H₂S may inhibit pro-inflammatory pathway, resulting in reduced production of pro-inflammatory mediators such as interleukin-1beta (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and intercellular adhesion molecule-1 (ICAM-1) while activating anti-inflammatory pathway which increases production of IL-10.