Investigation of the renin-angiotensin system in mice with sickle cell Anemia

• Grant number: 15/04485-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: July 01, 2015
• End date: December 31, 2016
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Nicola Amanda Conran Zorzetto
• Grantee: Pamela Lara de Brito
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 14/00984-3 - Red blood cell disorders: pathophysiology and new therapeutic approaches, AP.TEM

Abstract

Sickle cell anemia (SCA) is a genetic disease caused by the exchange of a glutamic acid for valine in position 6 of the²-globin chain, resulting in the production of hemoglobin S (HbS). HbS polymerizes under conditions of deoxygenation leading the erythrocyte to adopt a sickle shape. This event may result in vessel-occlusive processes leading to clinical complications in patients, among these the renal and cardiovascular disease, pain and death. With advancing age, many patients with SCA develop chronic renal failure. The kidneys are responsible for homeostasis and the modulation of blood pressure (BP) via the renin-angiotensin system (RAS). Renin cleaves angiotensinogen to angiotensin I (AngI), while the angiotensin converting enzyme (ACE) cleaves AngI to angiotensin II (AngII), a vasoconstrictor peptide that acts in the regulation of BP by modulating vasomotor tone and fluid balance. AngII is also involved in reducing the bioavailability of nitric oxide (NO), a vasodilator gas, contributing to the formation of reactive oxygen species and leading to endothelial alterations. Hydroxyurea (HU) is commonly used as a therapy in SCA, as it elevates levels of fetal hemoglobin (HbF), reducing the sickling of red blood cells; it also acts as a donor agent of NO and reduces leukocyte counts. ACE inhibitors (ACEi) and AngII receptor blockers are associated with treatment in some SCA patients with albuminuria, in order to prevent nephrologic disorders and the development of chronic kidney disease. Studies report that patients homozygous for HbS have a lower incidence of hypertension, demonstrating lower BP values, despite the fact that it is known that vasoconstrictor factors are increased in SCA. Although there are no reports of changes in the RAS in SCA patients, a study by our research group using an animal model of SCA identified changes in the levels of AngII and ACE in plasma of these animals, as well as changes in the expression of angiotensin II receptors (ATR) in some tissues. The objective of this study is to verify alterations in the RAS proteins in SCA and investigate an association of these alterations in remodeling of blood pressure and the development of renal injury in mice with SCA.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

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.; et al. Reduced blood pressure in sickle cell disease is associated with decreased angiotensin converting enzyme (ACE) activity and is not modulated by ACE inhibition. PLoS One, v. 17, n. 2, p. 19-pg., 2022-02-03. (17/03954-6, 14/00984-3, 15/04485-4)