Abnormal apelin-ACE2 and SGLT2 signaling contribute to adverse cardiorenal injury in patients with COVID-19

Abstract

Background: Angiotensin converting enzyme 2 (ACE2) has recently been identified as the functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent response for novel coronavirus disease 2019 . This study aimed to explore the roles of ACE2, apelin and sodium-glucose cotransporter 2 (SGLT2) in SARS-CoV-2-mediated cardiorenal damage. Methods and Results: The published RNA-sequencing datasets of cardiomyocytes infected with SARS-CoV-2 and COVID-19 patients were used. String, UMAP plots and single cell RNA sequencing data were analyzed to show the close relationship and distinct cardiorenal distribution patterns of ACE2, apelin and SGLT2. Intriguingly, there were decreases in ACE2 and apelin expression as well as marked increases in SGLT2 and endothelin-1 levels in SARS-CoV-2-infected cardiomyocytes, animal models with diabetes, acute kidney injury, heart failure and COVID-19 patients. These changes were linked with downregulated levels of interleukin (IL)-10, superoxide dismutase 2 and catalase as well as upregulated expression of profibrotic genes and pro-inflammatory cytokines/ chemokines. Genetic ACE2 deletion resulted in upregulation of pro-inflammatory cytokines containing IL-1β, IL-6, IL-17 and tumor necrosis factor α. More importantly, dapagliflozin strikingly alleviated cardiorenal fibrosis in diabetic db/db mice by suppressing SGLT2 levels and potentiating the apelin-ACE2 signaling. Conclusion: Downregulation of apelin and ACE2 and upregulation of SGLT2, endothelin-1 and pro-inflammatory cytokines contribute to SARS-CoV-2-mediated cardiorenal injury, indicating that the apelin-ACE2 signaling and SGLT2 inhibitors are potential therapeutic targets for COVID-19 patients.

Changes in serum levels of apelin and nitric oxide in hospitalized patients with COVID-19: association with hypertension, diabetes, obesity, and severity of disease

“…The lower serum apelin levels found in COV patients in this study can be a result of its degradation by ACE2 as circulatory ACE2 has been shown to be increased in patients with COVID-19 [30]. In an animal model of ARDS, there was a significant decrease in the level of apelin in blood and lung tissue [29], and ACE2 and apelin expressions decreased in cardiomyocytes infected by SARS-CoV-2 [27].…”

“…Therefore, it is suggested that lower apelin levels may worsen COVID-19 disease complications. Apelin can exert its effect directly by binding to APJ and acting on several signaling pathways in different tissues, including the respiratory and circulation system, and indirectly by enhancement of ACE2 expression [27,28]. In experimental models of ARDS, apelin inhibits pro-inflammatory cytokine production, reduces inflammation, and improves oxygenation by activation of AKI-eNOS pathways [29].…”

Susceptibility to recombinant SARS‐CoV‐2 spike protein entry in the lungs of high‐fat diet‐induced obese mice

“…50 Recent studies suggest possible beneficial effects of noninsulin antihyperglycemic agents against SARS-CoV-2 infection, such as dipeptidyl peptidase-4 inhibitors (DPP4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and glucagon-like peptide-1 (GLP-1) receptor agonists. [51][52][53][54][55] The current study has several limitations: (i) more examinations with human ACE2-transgenic mice might be considered to confirm the conclusion of this study. (ii) This experimental model is limited with respect to pathophysiology.…”

Discriminative Value of Serum Irisin in Prediction of Heart Failure with Different Phenotypes among Patients with Type 2 Diabetes Mellitus

“…To update our knowledge, the levels of irisin are regarded to be an attribute of the management of T2DM and HF. For instance, previous clinical studies have shown some benefit in cardiac myocyte protection due to an SGLT2 inhibitor-related increase in serum levels of various adipomyokines, such as apelin and irisin, and a decrease in myostatin in HF [ 58 , 59 , 60 ].…”