Modulações nos sistemas renina-angiotensina-aldosterona e calicreína-cinina contribuindo para alterações cardiometabólicas associadas à obesidade infantojuvenil
Data
2022-02-24
Autores
Cruz, Nayara Azinheira Nobrega
Orientadores
Casarini, Dulce Elena [UNIFESP]
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A obesidade infantojuvenil é um problema de saúde pública devido ao maior risco de
desenvolvimento precoce de doenças associadas como hipertensão, dislipidemias,
diabetes e síndrome metabólica. Há evidências de que o sistema renina-angiotensina-aldosterona
(SRAA) e o sistema calicreína-cinina (SCC) possam ser modulados na
obesidade. Objetivo: Avaliar a modulação do SRAA e do SCC em crianças e
adolescentes com diferentes estados nutricionais e avaliar a contribuição destas
alterações para desenvolvimento de complicações associadas a obesidade.
Métodos: Participantes de 6 a 19 anos foram classificados como baixo peso (BP),
eutrófico (EU), sobrepeso (SP) e obeso (OB) de acordo com o percentil do IMC.
Também foram classificados pelo risco cardiovascular de acordo com a razão cintura
e estatura (RCE). Foi realizada avaliação clínica e foram mensuradas a expressão e
atividade das enzimas; renina, enzima conversora de angiotensina (ECA), ECA2,
endopeptidase neutra, catepsina D (CatD) e quimase na urina e no
plasma. Resultados: Nas amostras de urina, a expressão da ECA somática (sECA)
estava aumentada no grupo OB quando comparado com o grupo EU (0,530 vs 0,090
unidade arbitrária, p=0,04) e foi maior no grupo com RCE aumentada (0,265 vs 0,090,
p =0,046). A isoforma N-domínio solúvel de 90 KDa da ECA (nECA de 90 KDa) foi
mais frequentemente encontrada no grupo com RCE aumentada (p=0,05), sua
expressão foi maior neste grupo (0,265 vs 0,130, p=0,02) e se correlacionou
positivamente com parâmetros antropométricos. A atividade da CatD urinária foi maior
no grupo EU do que no grupo SP (0,098 vs 0,027, p<0,01) e estava aumentada no
grupo com RCE normal (0,095 vs 0,028, p<0,01). A obesidade e a RCE aumentada
estavam relacionadas com a hipertrigliceridemia e a deficiência de HDL-C e houve
correlação entre a atividade da ECA urinária, a expressão da quimase urinária e a
expressão da CatD plasmática com estas alterações. O grupo OB apresentou maiores
níveis de ácido úrico, maior número de plaquetas e maiores valores pressóricos. O
último se correlacionou positivamente com a atividade da quimase urinária.
Conclusão: A obesidade e a RCE aumentada contribuíram para maior expressão da
sECA e da nECA de 90 na urina, e para uma menor atividade da CatD urinária, o que
pode refletir menor síntese de CatD à nível renal ou um menor clearance da CatD
circulante, culminando em seu acúmulo no plasma. Essas alterações podem promover
o aumento dos níveis de angiotensina (Ang) I e Ang II e a diminuição dos níveis de
Ang 1-7 e bradicinina. O desbalanço nos níveis destes peptídeos favorecem a
hipertrigliceridemia, o acúmulo dos triglicerídeos nos adipócitos e por fim, a
manutenção da obesidade. O aumento da expressão da ECA associado a
hipertrigliceridemia e deficiência de HDL-C contribuem para a inflamação, o estresse
oxidativo, a disfunção endotelial e a resistência à insulina; mecanismos que levam ao
desenvolvimento das dislipidemias, hipertensão, diabetes e síndrome metabólica.
Childhood obesity is a public health issue linked to a higher risk of developing obesity associated diseases as, hypertension, dyslipidemia, diabetes, and metabolic syndrome. There is evidence that the renin-angiotensin-aldosterone system (RAAS) and the kallikrein-kinin system (KKS) are modulated in obesity. Objectives: Evaluate the modulation of RAAS and KKS in children and adolescents with different nutritional status and evaluate the contribution of alterations in these systems to the development of obesity associated diseases. Methods: Participants aged from 6 to 19 years were classified into underweight (UW), normal weight (NW), overweight (OW) and obese (OB) according to body mass index percentile. They were also classified by cardiovascular risk assessed through waist to height ratio (WHtR). The clinical evaluation was performed, and we measured the expression and activity of renin, angiotensin converting enzyme (ACE), ACE2, neprilysin, cathepsin D (CatD) and chymase in urine and plasma samples. Results: In urine, expression of somatic ACE (sACE) was higher in OB than in NW group (0.530 vs 0.090 arbitrary unit, p=0,04) and it was increased in higher WHtR group (0.265 vs 0.090, p =0.046). The N-domain isoform of 90 KDa of ACE (nACE of 90 KDa) was more frequently found in the higher WHtR group (p=0.05), its expression was higher in this group (0.265 vs 0.130, p=0.02) and it positively correlated with anthropometric variables. The urinary CatD activity was increased in NW group compared to OW group (0.098 vs 0.027, p<0.01) and it was higher in normal WHtR group (0.095 vs 0.028, p<0.01). Obesity and higher WHtR were associated with hypertriglyceridemia and HDL-C deficiency and there was correlation between urinary ACE activity, urinary chymase expression and circulating CatD expression with these clinical alterations. The OB group presented higher levels of uric acid, increased number of platelets and augmented blood pressure values. The last was positively correlated with the expression of urinary chymase. Conclusion: Obesity and higher WHtR contributed to higher sACE and nACE of 90 KDa expression in urine and to lower urinary CatD activity what can be due to downregulation of CatD in the kidneys, or to decreased clearance of circulating CatD, resulting in its accumulation in plasma. These alterations can lead to higher levels of angiotensin (Ang) I and Ang II and diminished levels of Ang 1-7 and bradykinin. This imbalance contributes to the hypertriglyceridemia, triglycerides accumulation in the adipocytes and to obesity. The augmented expression of ACE associated to hypertriglyceridemia and HDL-C deficiency leads to inflammation, oxidative stress, endothelial dysfunction, and insulin resistance; mechanisms which contribute to the development of dyslipidemia, hypertension, diabetes, and metabolic syndrome.
Childhood obesity is a public health issue linked to a higher risk of developing obesity associated diseases as, hypertension, dyslipidemia, diabetes, and metabolic syndrome. There is evidence that the renin-angiotensin-aldosterone system (RAAS) and the kallikrein-kinin system (KKS) are modulated in obesity. Objectives: Evaluate the modulation of RAAS and KKS in children and adolescents with different nutritional status and evaluate the contribution of alterations in these systems to the development of obesity associated diseases. Methods: Participants aged from 6 to 19 years were classified into underweight (UW), normal weight (NW), overweight (OW) and obese (OB) according to body mass index percentile. They were also classified by cardiovascular risk assessed through waist to height ratio (WHtR). The clinical evaluation was performed, and we measured the expression and activity of renin, angiotensin converting enzyme (ACE), ACE2, neprilysin, cathepsin D (CatD) and chymase in urine and plasma samples. Results: In urine, expression of somatic ACE (sACE) was higher in OB than in NW group (0.530 vs 0.090 arbitrary unit, p=0,04) and it was increased in higher WHtR group (0.265 vs 0.090, p =0.046). The N-domain isoform of 90 KDa of ACE (nACE of 90 KDa) was more frequently found in the higher WHtR group (p=0.05), its expression was higher in this group (0.265 vs 0.130, p=0.02) and it positively correlated with anthropometric variables. The urinary CatD activity was increased in NW group compared to OW group (0.098 vs 0.027, p<0.01) and it was higher in normal WHtR group (0.095 vs 0.028, p<0.01). Obesity and higher WHtR were associated with hypertriglyceridemia and HDL-C deficiency and there was correlation between urinary ACE activity, urinary chymase expression and circulating CatD expression with these clinical alterations. The OB group presented higher levels of uric acid, increased number of platelets and augmented blood pressure values. The last was positively correlated with the expression of urinary chymase. Conclusion: Obesity and higher WHtR contributed to higher sACE and nACE of 90 KDa expression in urine and to lower urinary CatD activity what can be due to downregulation of CatD in the kidneys, or to decreased clearance of circulating CatD, resulting in its accumulation in plasma. These alterations can lead to higher levels of angiotensin (Ang) I and Ang II and diminished levels of Ang 1-7 and bradykinin. This imbalance contributes to the hypertriglyceridemia, triglycerides accumulation in the adipocytes and to obesity. The augmented expression of ACE associated to hypertriglyceridemia and HDL-C deficiency leads to inflammation, oxidative stress, endothelial dysfunction, and insulin resistance; mechanisms which contribute to the development of dyslipidemia, hypertension, diabetes, and metabolic syndrome.