Is the kidney a target of SARS-CoV-2?

Abstract

The new disease produced by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) represents a major pandemic event nowadays. Since its origin in China in December 2019, there is compelling evidence that novel SARS-CoV-2 is a highly transmissible virus, and it is associated to a broad clinical spectrum going from subclinical presentation to severe respiratory distress and multiorgan failure. Like other coronaviruses, SARS-CoV-2 recognizes human angiotensin-converting enzyme 2 as a cellular receptor that allows it to infect different host cells and likely disrupts renin-angiotensin-aldosterone system homeostasis. Particularly, a considerable incidence of many renal abnormalities associated to COVID-19 has been reported, including proteinuria, hematuria, and acute kidney injury. Moreover, it has been recently demonstrated that SARS-CoV-2 can infect podocytes and tubular epithelial cells, which could contribute to the development of the aforementioned renal abnormalities. In this review, we discuss the biological aspects of SARS-CoV-2 infection, how understanding current knowledge about SARS-CoV-2 infection may partly explain the involvement of the kidneys in the pathophysiology of COVID-19, and what questions have arisen and remain to be explored.

Keywords: COVID-19; acute kidney injury; angiotensin-converting enzyme 2; proteinuria; renin-angiotensin-aldosterone system.

Fig. 1.

Cellular infection by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus recognizes human angiotensin-converting enzyme 2 (hACE2) in the apical membrane of type II pneumocytes with domain B of S1 in the protein Spike (S). It can then take the endocytic pathway or the plasma membrane pathway. In the former, the virion is internalized in a phagosome, where S suffers proteolysis by host proteases, which generates conformational changes that expose the fusion peptides HR1 and HR2 located within S2. In the plasma membrane pathway, proteases with extracellular domain cleave S outside the cell immediately after the binding to ACE2. When HR1 and HR2 are exposed, whether inside the phagosome or in the plasma membrane, they mediate the fusion of host and virion membranes, allowing the release of viral RNA into the cytosol and the early expression of viral genes. Some of these viral proteins are thought to induce the formation of a reticular complex originated from the endoplasmic reticulum. This complex and the double-membrane vesicles inside it constitute the molecular factory of new virions. After assembly of the different components of the newly formed virions, they are secreted outside cell, and the cycle begins once again.

Fig. 2.

Possible mechanisms of kidney damage by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) expression in podocytes makes the glomerulus a direct target of SARS-CoV2 infection, leading to podocyte vacuolation, foot process effacement, and cell detachment. In addition, the occupation of ACE2 by SARS-CoV-2 could prevent angiotensin II clearance, which could contribute even more to podocyte dysfunction. ACE2 in proximal epithelial cells also makes them a direct target of SARS-CoV-2 infection and virus-related injury. This process could be aggravated by an uncontrolled systemic inflammatory response involving a cytokine storm and local inflammation. (This image was created with Biorender.) hACE2, human ACE2; AT1R, angiotensin II type 1 receptor; AKI, acute kidney injury.