Regulation of SARS CoV-2 host factors in the kidney and heart in rats with 5/6 nephrectomy: Effects of salt, ARB, dipeptidyl peptidase 4 inhibitor, and SGLT-2 blocker

ABSTRACT

Background: Host factors such as angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease, serine subtype 2 (TMPRSS2) are important factors for SARSCoV-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-inhibitors 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+2% 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) was not affected, whereas the cardiac level was significantly increased in 5/6 Nx rats. Intriguingly, the elevated TMPRSS2 protein expression in the heart was significantly normalized after treatment with telmisartan, linagliptin and empagliflozin. Conclusions: Overall, our study indicated that there is no upregulation regarding host factors potentially promoting SARS CoV-2 virus entry into host cells when the SGLT2 inhibitor empagliflozin, telmisartan and the DPP4 blocker linagliptin are used. The results obtained in a preclinical, experimental non-diabetic kidney failure model need confirmation in ongoing interventional clinical trials.