Expressão e atividade da enzima conversora da angiotensina I como biomarcador de hipertensão, Na urina de receptores de transplante renal pediátricos
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Data
2018-03-29
Autores
Pignatari, Maria Cecilia [UNIFESP]
Orientadores
Casarini, Dulce Elena [UNIFESP]
Tipo
Tese de doutorado
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A hipertensão pediátrica é um fator de risco para hipertensão nos adultos com prevalência entre 1 e 5%. Seu componente hereditário é estimado em 50%. A hipertensão primária resulta de fatores genéticos, ambientais e comportamentais. O Sistema Renina Angiotensina é importante para o controle cardiovascular e da função renal. A Enzima Conversora da Angiotensina (ECA) tem as isoformas somática N- e C- domínio (130-190 kDa) e testicular C- domínio (90-110 kDa). Casarini e cols. descreveram a isoforma N-domínio de 90 kDa na urina de humanos hipertensos como um possível biomarcador de hipertensão. OBJETIVOS: Analisar a expressão e atividade das isoformas da ECA na urina de receptores de transplante renal pediátricos antes e após o transplante e urina do doador, para verificar a transmissão da isoforma de 90 kDa e correlacionar com a hipertensão. MÉTODOS: 30 receptores pediátricos de transplante renal com doadores vivos; a atividade da ECA foi realizada antes, 1, 3 e 6 meses após o transplante usando ZPhe-HL e HHL como substratos e sua razão. Análise do Western blotting para avaliar as isoformas da ECA (190,90 e 65 kDa). RESULTADOS: 69% tinham hipertensão pré-transplante e 85,7% história familiar de hipertensão. Após seis meses, 25% permaneceram hipertensos. Do pré-transplante até o sexto mês após, a atividade da ECA reduziu. No modelo de regressão linear com efeitos aleatórios entre atividade da ECA e diversas variável s, incluindo o pré-transplante, para o substrato ZPhe-HL permaneceram significantes tempo, e uropatia com maior atividade da ECA (0,023 mU/mg creatinina a mais); com HHL, tempo e uropatia (0.019 mU/mg creatinina a mais) e o peso com redução da atividade da ECA (0.00038 mU/mg creatinina a cada 1 kg de aumento no peso). No pós-transplante somente o tempo e o peso permaneceram significantes com ZPhe-HL e para o HHL, uropatia, proteinúria (0,010 mU/mg creatinina a mais da atividade) e peso. Receptores antes do transplante tinham mais alta atividade da ECA urinária quando comparados com controles. Dados do Western blotting mostraram que todos os receptores sem ECA de 90 kDa quando receberam um rim de doador que tinha essa isoforma começaram a expressá-la.CONCLUSÃO: O aumento da atividade da ECA nas uropatias pode ser associada com injúria renal ou produção intra-renal. A proteinúria, um marcador de lesão renal, pode ser associada com o aumento da atividade da ECA. Com a recuperação nutricional e um rim saudável após o transplante, os receptores podem reverter o grau de lesão renal e diminuir a produção da ECA. A análise de Western blotting demonstrou que 100% dos receptores sem a isoforma de 90 kDa pré-transplante, cujos doadores apresentavam essa isoforma, passaram a expressá-la após o transplante, sugerindo uma transmissão do perfil biológico ao receptor.
Pediatric hypertension is a risk factor for hypertension in adults with prevalence between 1 and 5%. Its hereditary component is estimated at 50 %. Primary hypertension results from genetic, environmental, and behavioral factors. Renin Angiotensin System is important to control cardiovascular and renal functions. Angiotensin Converting Enzyme (ACE) has isoforms: somatic N- and C- domain (130-190 kDa) and testicular C-domain (90-110 kDa). Casarini et al. described the N-domain isoform of 90kDa, in urine of hypertensive humans as a possible hypertension biomarker. OBJECTIVE: Analyze the expression and activity of ACE isoforms in urine of pediatric renal transplant recipients before and after transplantation and urine of donor, to verify the 90 kDa isoform transmission and correlating with hypertension. METHODS: 30 pediatric renal transplant recipients with living donors; ACE activity was performed before, 1, 3 and 6 months post transplantation using ZPhe-HL and HHL as substrates and its ratio. Western blotting analysis to evaluate ACE isoforms (190, 90 and 65kDa). RESULTS: 69% had pretransplant hypertension and 85.7% family history of hypertension. After 6 months 25% remained hypertensive. From the pre-transplant until the sixth month after, ACE activity was reduced. In the linear regression model with random effects between ACE activity and various variables, including pre-transplantation for the substrate ZPhe-HL remained significant time, and uropathy with higher activity of ACE (0.023 mU/mg creatinine more); with HHL, time and uropathy (0.019 mU/mg creatinine more) and for weight, reduction of ACE activity (0.00038 mU/mg creatinine at 1 kg increase in weight). At post-transplant only time and weight remained significant with ZPhe-HL, and for HHL, uropathy, proteinuria (0.010 mU/mg creatinine more ACE activity) and weight. Recipients before transplantation had higher urinary ACE activity when compared to controls. Western blotting data showed that all recipients without ACE 90KDa when received a kidney from the donor that had this isoform, started to express it. CONCLUSIONS: Increased ACE activity in uropathies may be associated with renal injury or intra-renal production. Proteinuria, a marker of renal injury, can be associated with increase on ACE activity. With nutritional recovery and a healthy kidney after transplantation, recipients can reverse the degree of renal damage and decrease the production of ACE. The Western blotting analysis demonstrated that 100% of the recipients without the pre-transplantation isoform of 90 kDa, whose donors had this isoform, started to express it after transplantation, suggesting a transmission of the biological profile to the recipient.
Pediatric hypertension is a risk factor for hypertension in adults with prevalence between 1 and 5%. Its hereditary component is estimated at 50 %. Primary hypertension results from genetic, environmental, and behavioral factors. Renin Angiotensin System is important to control cardiovascular and renal functions. Angiotensin Converting Enzyme (ACE) has isoforms: somatic N- and C- domain (130-190 kDa) and testicular C-domain (90-110 kDa). Casarini et al. described the N-domain isoform of 90kDa, in urine of hypertensive humans as a possible hypertension biomarker. OBJECTIVE: Analyze the expression and activity of ACE isoforms in urine of pediatric renal transplant recipients before and after transplantation and urine of donor, to verify the 90 kDa isoform transmission and correlating with hypertension. METHODS: 30 pediatric renal transplant recipients with living donors; ACE activity was performed before, 1, 3 and 6 months post transplantation using ZPhe-HL and HHL as substrates and its ratio. Western blotting analysis to evaluate ACE isoforms (190, 90 and 65kDa). RESULTS: 69% had pretransplant hypertension and 85.7% family history of hypertension. After 6 months 25% remained hypertensive. From the pre-transplant until the sixth month after, ACE activity was reduced. In the linear regression model with random effects between ACE activity and various variables, including pre-transplantation for the substrate ZPhe-HL remained significant time, and uropathy with higher activity of ACE (0.023 mU/mg creatinine more); with HHL, time and uropathy (0.019 mU/mg creatinine more) and for weight, reduction of ACE activity (0.00038 mU/mg creatinine at 1 kg increase in weight). At post-transplant only time and weight remained significant with ZPhe-HL, and for HHL, uropathy, proteinuria (0.010 mU/mg creatinine more ACE activity) and weight. Recipients before transplantation had higher urinary ACE activity when compared to controls. Western blotting data showed that all recipients without ACE 90KDa when received a kidney from the donor that had this isoform, started to express it. CONCLUSIONS: Increased ACE activity in uropathies may be associated with renal injury or intra-renal production. Proteinuria, a marker of renal injury, can be associated with increase on ACE activity. With nutritional recovery and a healthy kidney after transplantation, recipients can reverse the degree of renal damage and decrease the production of ACE. The Western blotting analysis demonstrated that 100% of the recipients without the pre-transplantation isoform of 90 kDa, whose donors had this isoform, started to express it after transplantation, suggesting a transmission of the biological profile to the recipient.
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Citação
PIGNATARI, Maria Cecília. Expressão e atividade da enzima conversora da angiotensina I como biomarcador de hipertensão, na urina de receptores de transplante renal pediátricos. 2018. 85 f. Tese (Doutorado em Medicina: nefrologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 2018.