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| Author(s): |
Pâmela Lara de Brito
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2019-01-30 |
| Examining board members: |
Nicola Amanda Conran Zorzetto;
Margareth Castro Ozelo;
Maria Stella Figueiredo
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| Advisor: | Nicola Amanda Conran Zorzetto |
| Abstract | |
Sickle cell anemia (SCA) is a hereditary hematological disease that affects the HBB (beta subunit of hemoglobin) gene, leading to the synthesis of abnormal hemoglobin S (HbS). At low oxygen concentrations, HbS polymerizes and the red blood cell (RBC) adopts a characteristically sickled shape. Together with hemolytic processes, these RBC with altered physico-chemical properties, incur vascular inflammation and, eventually, the vaso-occlusive (VO) processes that characterize the disease. One of the main clinical complications of SCA is renal dysfunction, which provokes high rates of morbidity and mortality in these patients. The constant sickling of RBC and VO processes in the renal medulla can lead to the obstruction of blood flow in the vessels and renal ischemia. The Renin-Angiotensin System (RAS) regulates the formation of angiotensin II (Ang II) in response to hemodynamic changes, promoting vasoconstriction and fluid balance in order to normalize blood pressure (BP). The purpose of this study was to investigate changes in RAS and renal changes in a mouse model of SCA at different ages. In addition, we aimed to observe possible alterations in the BP of these animals and changes in this measurement during aging, to evaluate a possible association between altered BP and changes in RAS in these animals. Finally, the modulation of these parameters using therapy with enalapril, an angiotensin converting enzyme inhibitor (ACE 1), was evaluated. For this, chimeric SCA (Berkeley) and chimeric control (C57BL6) male mice (denominated CBERK and CCON) were evaluated at the ages of 5 months and 9 months (corresponding to the young adult and adult phases, respectively). Diuresis, water ingestion and proteinuria were measured using 24h-urine samples. Plasma Ang II, ACE 1 and renin were quantified by ELISA, and the renal distribution of these proteins and morphological analysis of tissues was analyzed by immuno/histochemistry. The BP of the animals was monitored using a noninvasive method (NIBP). Finally, CBERK and CCON (5-months old) were treated with enalapril (25mg /kg /day) for 5 weeks and these parameters were reevaluated. The analysis of urinary parameters showed that CBERK young adult mice showed a significant increase in proteinuria and urine density, compared to CCON of the same ages. In addition, CBERK mice also had lower diuresis and water intake at both ages. Histological analysis showed augmented glomerular hypertrophy and mesangial expansion in adulthood in the CBERK groups, compared to age-matched CCON mice. The plasma levels of Ang II and ACE 1 were significantly reduced in adult CBERK animals, while plasma renin was significantly higher in CBERK animals (adults and young adults), when compared to age-matched CCON mice. Immunohistochemistry showed that there were no differences in the distributions of angiotensin, ACE 1, and renin in the kidneys of CBERK animals, compared to CCON. BP was significantly lower in the young adult and adult CBERK groups, compared to the CCON animals of the same ages. However, these alterations in BP did not present statistical correlation with Ang II, ACE 1 and plasma renin. Treatment with enalapril significantly reduced proteinuria and elevated water intake and diuresis in CBERK animals, compared to untreated CBERK animals. Increases in levels of Ang II, and ACE 1 were observed in CBERK mice receiving enalapril compared to untreated mice; however, these increases were not significant. Conversely, CCON mice treated with enalapril demonstrated significantly reduced Ang II, and ACE-1, compared to untreated 5-month old CCON mice. Plasma renin concentrations did not change significantly in the treated CBERK and CCON groups, and treatment with enalapril did not modify the BP values of either the CBERK or CCON groups, compared to the untreated groups. These data indicate that adult mice with SCA present significant alterations in their production of circulating RAS proteins, in association with decreased PA and renal damage. Further studies are needed to confirm a role for the RAS in the relatively lower PA that is observed in patients with SCA. Importantly, treatment of SCA mice with an ACE inhibitor, to improve proteinuria, did not further decrease PA in these mice and this treatment was not associated with significant changes in circulating RAS protein concentrations. These findings further our understanding of a possible involvement of RAS in the altered PA that is associated with SCA and provide data regarding the clinical implications of the use of ACE inhibitor therapy in SCA (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 |