Reduced blood pressure in sickle cell disease is associated with decreased angiotensin converting enzyme (ACE) activity and is not modulated by ACE inhibition

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Brito, Pamela L. ; Dos Santos, Alisson F. ; Chweih, Hanan ; Favero, Maria E. ; Gotardo, Erica M. F. ; Silva, Juliete A. F. ; Leonardo, Flavia C. ; Franco-Penteado, Carla F. ; de Oliveira, Mariana G. ; Ferreira Jr, Wilson A. ; Zaidan, Bruna C. ; Billis, Athanase ; Baldanzi, Giorgio ; Mashima, Denise A. ; Antunes, Edson ; Saad, Sara T. Olalla ; Costa, Fernando F. ; Conran, Nicola

• Document type: Journal article
• Source: PLoS One; v. 17, n. 2, p. 19-pg., 2022-02-03.

Abstract

Background Sickle cell disease (SCD) incurs vaso-occlusive episodes and organ damage, including nephropathy. Despite displaying characteristics of vascular dysfunction, SCD patients tend to present relatively lower systemic blood pressure (BP), via an unknown mechanism. We investigated associations between BP and renin-angiotensin-system (RAS) components in SCD and determined whether an inhibitor of angiotensin converting enzyme (ACE; often used to slow SCD glomerulopathy) further modulates BP and RAS components in a murine model of SCD. Methods BP was compared in human subjects and mice with/without SCD. Plasma angiotensin II, ACE and renin were measured by immunoassay. BP was reevaluated after treating mice with enalapril (25 mg/kg, 5x/week) for 5 weeks; plasma and organs were stored for angiotensin II and ACE activity measurement, and quantitative real-time PCR. Results Diastolic BP and systolic BP were significantly lower in patients and mice with SCD, respectively, compared to controls. Reduced BP was associated with increased plasma renin and markers of kidney damage (mice) in SCD, as well as significantly decreased plasma ACE concentrations and ACE enzyme activity. As expected, enalapril administration lowered BP, plasma angiotensin II and organ ACE activity in control mice. In contrast, enalapril did not further reduce BP or organ ACE activity in SCD mice; however, plasma angiotensin II and renin levels were found to be significantly higher in enalapril-treated SCD mice than those of treated control mice. Conclusion Relative hypotension was confirmed in a murine model of SCD, in association with decreased ACE concentrations in both human and murine disease. Given that ACE inhibition has an accepted role in decreasing BP, further studies should investigate mechanisms by which ACE depletion, via both Ang II-dependent and alternative pathways, could contribute to reduce BP in SCD and understand how ACE inhibition confers Ang II-independent benefits on kidney function in SCD. (AU)

• FAPESP's process: 17/03954-6 - Evaluation of blood pressure and changes in the renin-angiotensin system in an animal model of sickle cell anemia
• Grantee: Pamela Lara de Brito
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 14/00984-3 - Red blood cell disorders: pathophysiology and new therapeutic approaches
• Grantee: Fernando Ferreira Costa
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/04485-4 - Investigation of the renin-angiotensin system in mice with sickle cell Anemia
• Grantee: Pamela Lara de Brito
• Support Opportunities: Scholarships in Brazil - Scientific Initiation