Abstract
Diabetics are more vulnerable to SARS-CoV-2 cerebrovascular complications, including brain fog, cognitive impairment, and strokes. This study aims to identify the molecular mechanisms of SARS-CoV-2-induced cerebrovascular dysfunction in diabetes. We hypothesize that SARS-CoV-2 exacerbates diabetes-induced cerebral oxidative stress and inflammation via activation of the destructive arm of the renin-angiotensin system (RAAS) and Toll-Like receptor (TLR) signaling. Methods: SARS-CoV-2 spike-protein binds to human angiotensin-converting enzyme-2 (ACE2) receptors but not murine Ace2. Therefore, type-2 diabetes was induced in humanized ACE2 (hACE2) knock-in transgenic mice using low-dose streptozotocin followed by eight weeks of a high-fat diet. Recombinant SARS-CoV-2 spike-protein was injected intravenously in control and diabetic mice. Cognitive functions were tested using Y-maze and Barnes maze. RAAS system and TLR signaling were assessed using RT-PCR and western blot analysis. The cerebrovascular architecture was measured using immunohistochemistry. Results: Diabetes increased cerebrovascular oxidative stress markers NOX1 and NOX5 and inflammatory markers Il-6, Il-1β, and TNF-α gene expression (P<0.05). Diabetes upregulated angiotensin II and angiotensin 1 receptor (AT1R) expression, these effects were amplified by spike-protein (P<0.05). Moreover, spike-protein injection decreased RAAS protective arm, ACE2, and AT2R expression (P<0.05). In parallel, spike-protein exacerbated TLR signaling in diabetes. Spike-protein increased the TLR-8 receptors and its ligands HMGB1 and S100 and downstream adaptor proteins MyD88, TRAF6, and NF-κB expression (P<0.05). Spike-protein significantly increased cerebrovascular rarefaction and cognitive dysfunction in diabetes (P<0.05). Conclusion: SAR-CoV-2 spike-protein intensified RAAS and TLR signaling in diabetes leading to additional cerebrovascular damage and cognitive dysfunction. Targeting RAAS and TLR singling are possible therapeutic strategies to protect against SAR-CoV-2-induced cerebrovascular dysfunction in diabetes.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
