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Doctoral Thesis
DOI
10.11606/T.5.2018.tde-28092018-120959
Document
Author
Full name
Cynthia Rodrigues Müller
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2018
Supervisor
Committee
Evangelista, Fabiana de Sant'Anna (President)
Medeiros, Alessandra
Andrade, Lucia da Conceição
Boim, Mirian Aparecida
Title in Portuguese
Potencial do treinamento físico para a prevenção de danos renais em camundongos: papel da proteína ativada por AMP (AMPK)
Keywords in Portuguese
Doença renal crônica
Lipídeos
Proteína ativada por AMP (AMPK)
Sistema renina-angiotensina
Abstract in Portuguese
O acúmulo de lipídeos associado à obesidade, resistência à insulina (RI) e diabetes mellitus tipo 2 (DM2) pode levar ao desenvolvimento de danos renais, e diversos mecanismos podem estar envolvidos neste processo, dentre os quais: 1) redução na atividade da proteína ativada por AMP (AMPK); 2) hiperativação do sistema renina angiotensina (SRA) e consequente aumento na produção de angiotensina II (Ang II). O treinamento físico aeróbio (TFA) promove melhora metabólica significativa, no entanto, pouco se sabe sobre os mecanismos celulares induzidos pelo TFA contra o desenvolvimento de danos renais associados com doenças metabólicas. Sendo assim, o objetivo deste estudo foi avaliar o potencial do TFA para a prevenção de danos renais induzidos por dieta de cafeteria, e a participação do SRA e da proteína AMPK nessa resposta. Para isso, camundongos machos adultos C57BL6/J foram separados em grupos (n=13/grupo) sedentários (SED) alimentados com dieta normocalórica (NO) ou de cafeteria (CAF) (SED-NO e SED-CAF, respectivamente) e treinados (TF) alimentados com dieta NO ou CAF (TF-NO e TF-CAF, respectivamente). O TFA foi realizado a 60% da capacidade máxima, simultaneamente com as dietas durante 8 semanas. A dieta de cafeteria causou maior adiposidade, intolerância à glicose e RI no grupo SED-CAF, enquanto o TFA preveniu esses prejuízos no grupo TF-CAF. Os animais SED-CAF apresentaram 88% de aumento no ritmo de filtração glomerular (RFG), maior deposição lipídica renal e redução do espaço de Bowman comparado ao SED-NO, as quais foram prevenidas no grupo TF-CAF. Não houve alteração no conteúdo de colágeno IV e fibronectina, entretanto o TNF-alfa aumentou em ambos os grupos alimentados com dieta de cafeteria. Houve aumento de 27% da expressão proteica da p-AMPK no grupo TF-CAF, sem diferenças na expressão de t-ACC, p-ACC, PGC1-alfa e SIRT-1. A expressão gênica do SREBP-1 não diferiu entre os grupos, porém a expressão do SREBP-2 aumentou nos grupos SED-CAF e TF-CAF comparado aos grupos SED-NO e TF-NO. No soro, apenas a atividade da ECA2 aumentou nos grupos TF-NO e TF-CAF comparados aos sedentários. No rim, a atividade da ECA aumentou 46% no grupo SED-CAF comparado ao SED-NO, e o TFA foi capaz de prevenir esse aumento. No entanto, a Ang II renal aumentou nos grupos SED-CAF, TF-NO e TF-CAF comparados ao grupo SED-NO. Não houve diferença nos componentes do SRA ECA2/Ang 1-7/Mas renal. Em conclusão, o TFA preveniu os danos renais causados pela dieta de cafeteria, tais como acúmulo de lipídeos nos rins, aumento do RFG e redução do espaço de Bowman, e essa resposta está associada, pelo menos em parte, com a maior ativação da AMPK independente da contribuição do SRA
Title in English
Potential of aerobic exercise training to prevent kidney damage in mice: the role of AMP-activated protein (AMPK)
Keywords in English
AMP-activated protein kinase (AMPK)
Chronic kidney disease
Lipids
Renin-angiotensin system
Abstract in English
Lipid accumulation observed in the obesity, insulin resistance (IR) and Diabetes Mellitus type 2 (DM2) may lead to the development of renal damage, and several mechanisms may be involved in this process, such as: 1) reduction in the AMP-activated protein (AMPK) activity; 2) hyperactivation of the renin angiotensin system (RAS) and consequent increase in the production of Angiotensin II (Ang II). Aerobic exercise training (AET) promotes significant metabolic improvement, however, little is known about the cellular mechanisms induced by AET against the development of kidney damage associated with metabolic diseases. Thus, the present study aimed to evaluate the potential of AET to prevent kidney damage induced by cafeteria diet, and the participation of RAS and AMPK protein in this response. Adult male C57BL6/J mice were separated into sedentary (SED) groups fed a normocaloric (NO) or cafeteria (CAF) (SED-NO and SED-CAF, respectively) and trained (TF) fed a NO or CAF diet (TF-NO and TF-CAF, respectively). The AET was performed at 60% of the maximum capacity simultaneously with the diets during 8 weeks. The cafeteria diet induced adiposity increase, glucose intolerance and IR, while AET prevented these changes. Animals SED-CAF increased 88% of glomerular filtration rate (GFR), increased renal lipid deposition and reduced Bowman's space compared to SED-NO, which were prevented by AET in the TF-CAF group. There was no change in the collagen IV and fibronectin, however TNF-alpha increased in both cafeteria diet fed groups. There was a 27% increase in the protein p-AMPK expression in the TF-CAF group, with no changes in t-ACC, p-ACC, PGC1-alpha and SIRT-1 expression. The SREBP-1 gene expression did not change among groups, but SREBP-2 gene expression increased in the SED-CAF and TF-CAF groups compared to the SED-NO and TF-NO groups. In the serum, only the activity of ACE 2 increased in TF-NO and TF-CAF groups compared to sedentary groups. In the kidney, ACE activity increased 46% in the SED-CAF group compared to SED-NO, nevertheless the AET was able to prevent this increase. Renal Ang II concentration increased in SED-CAF, TF-NO and TF-CAF groups compared to the SED-NO. No differences were observed in the components of renal RAS ACE2/Ang 1-7/Mas. In conclusion, AET prevented the renal damage caused by cafeteria diet, such as lipid accumulation, increased GFR and reduced Bowman space, and these responses are associated, at least in part, with greater activation of the AMPK protein independent of the RAS contribution
 
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Publishing Date
2018-09-28
 
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