Cardiac dysfunction in Pkd1-deficient mice with phenotype rescue by galectin-3 knockout

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Balbo, Bruno E. ; Amaral, Andressa G. ; Fonseca, Jonathan M. ; de Castro, Isac ; Salemi, Vera M. ; Souza, Leandro E. ; dos Santos, Fernando ; Irigoyen, Maria C. ; Qian, Feng ; Chammas, Roger ; Onuchic, Luiz F.

• Tipo de documento: Artigo Científico
• Fonte: Kidney International; v. 90, n. 3, p. 580-597, SEP 2016.
• Citações Web of Science: 5

Resumo

Alterations in myocardial wall texture stand out among ADPKD cardiovascular manifestations in hypertensive and normotensive patients. To elucidate their pathogenesis, we analyzed the cardiac phenotype in Pkd1(cond/cond) Nestin(cre) (CYG+) cystic mice exposed to increased blood pressure, at 5 to 6 and 20 to 24 weeks of age, and Pkd1(+/-) (HTG+) noncystic mice at 5-6 and 10-13 weeks. Echocardiographic analyses revealed decreased myocardial deformation and systolic function in CYG+ and HTG+ mice, as well as diastolic dysfunction in older CYG+ mice, compared to their Pkd1(cond/cond) and Pkd1(+/+) controls. Hearts from CYG+ and HTG+ mice presented reduced polycystin-1 expression, increased apoptosis, and mild fibrosis. Since galectin-3 has been associated with heart dysfunction, we studied it as a potential modifier of the ADPKD cardiac phenotype. Double-mutant Pkd1(cond/cond):Nestin(cre);Lgals(3-/-) (CYG-) and Pkd1(+/-);Lgals(3-/-) (HTG-) mice displayed improved cardiac deformability and systolic parameters compared to single -mutants, not differing from the controls. CYG- and HTG- showed decreased apoptosis and fibrosis. Analysis of a severe cystic model (Pkd1(v/v); VVG+) showed that Pkd1(v/v);Lgals(3-/-) (VVG-) mice have longer survival, decreased cardiac apoptosis and improved heart function compared to VVG+. CYG- and VVG- animals showed no difference in renal cystic burden compared to CYG+ and VVG+ mice. Thus, myocardial dysfunction occurs in different Pkdl-deficient models and suppression of galectin-3 expression rescues this phenotype. (AU)

• Processo FAPESP: 10/17424-0 - Bases da Hipertensão Arterial e de Disfunções Renais Associadas à Doença Renal Policística Autossômica Dominante: Estudo em Modelos Distintos de Deficiência do Gene Pkd1 em Camundongos
• Beneficiário: Luiz Fernando Onuchic
• Modalidade de apoio: Auxílio à Pesquisa - Regular