Key result
Telmisartan, linagliptin, and empagliflozin did not upregulate SARS-CoV-2 host factors ACE2 and TMPRSS2 in the kidney, and normalized elevated cardiac TMPRSS2 protein expression in 5/6 nephrectomy rats.
Why the study?
It was unknown whether DPP-4 inhibitors or SGLT2 blockers might promote COVID-19 by increasing the host viral entry enzymes ACE2 and TMPRSS2.
Do telmisartan, linagliptin, or empagliflozin upregulate the expression of SARS-CoV-2 host factors (ACE2, TMPRSS2) in the kidney and heart of 5/6 nephrectomized rats on a high-salt diet?
Do telmisartan, linagliptin, or empagliflozin upregulate the expression of SARS-CoV-2 host factors (ACE2, TMPRSS2) in the kidney and heart of 5/6 nephrectomized rats on a high-salt diet?
In a rat model of chronic kidney disease, treatment with telmisartan, linagliptin, or empagliflozin did not upregulate SARS-CoV-2 host entry factors (ACE2, TMPRSS2) and normalized elevated cardiac TMPRSS2 levels, supporting their safety during the COVID-19 pandemic.
BACKGROUND: Host factors such as angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease, serine-subtype-2 (TMPRSS2) are important factors for SARS-CoV-2 infection. Clinical and pre-clinical studies demonstrated that RAAS-blocking agents can be safely used during a SARS-CoV-2 infection but it is unknown if DPP-4 inhibitors or SGLT2-blockers may promote COVID-19 by increasing the host viral entry enzymes ACE2 and TMPRSS2. METHODS: We investigated telmisartan, linagliptin and empagliflozin induced effects on renal and cardiac expression of ACE2, TMPRSS2 and key enzymes involved in RAAS (REN, AGTR2, AGT) under high-salt conditions in a non-diabetic experimental 5/6 nephrectomy (5/6 Nx) model. In the present study, the gene expression of Ace2, Tmprss2, Ren, Agtr2 and Agt was assessed with qRT-PCR and the protein expression of ACE2 and TMPRSS2 with immunohistochemistry in the following experimental groups: Sham + normal diet (ND) + placebo (PBO); 5/6Nx + ND + PBO; 5/6Nx + high salt-diet (HSD) + PBO; 5/6Nx + HSD + telmisartan; 5/6Nx + HSD + linagliptin; 5/6Nx + HSD + empagliflozin. RESULTS: In the kidney, the expression of Ace2 was not altered on mRNA level under disease and treatment conditions. The renal TMPRSS2 levels (mRNA and protein) were not affected, whereas the cardiac level was significantly increased in 5/6Nx rats. Intriguingly, the elevated TMPRSS2 protein expression in the heart was significantly normalized after treatment with telmisartan, linagliptin and empagliflozin. CONCLUSIONS: Our study indicated that there is no upregulation regarding host factors potentially promoting SARS-CoV-2 virus entry into host cells when the SGLT2-blocker empagliflozin, telmisartan and the DPP4-inhibitor blocker linagliptin are used. The results obtained in a preclinical, experimental non-diabetic kidney failure model need confirmation in ongoing interventional clinical trials.
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Xiong et al. (2022) studied 5/6 nephrectomy (chronic kidney disease model) (n=91). Telmisartan, linagliptin, and empagliflozin vs. Placebo was evaluated on Renal and cardiac expression of ACE2 and TMPRSS2. Telmisartan, linagliptin, and empagliflozin did not upregulate SARS-CoV-2 host factors ACE2 and TMPRSS2 in the kidney, and normalized elevated cardiac TMPRSS2 protein expression in 5/6 nephrectomy rats.
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