title: Cardiac dysfunction in Pkd1-deficient mice with phenotype rescue by galectin-3 knockout.
abstract: 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);Lgals3(-/-) (CYG-) and Pkd1(+/-);Lgals3(-/-) (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);Lgals3(-/-) (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 Pkd1-deficient models and suppression of galectin-3 expression rescues this phenotype.
authors.affiliation: Division of Nephrology and Molecular Medicine, Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Bruno E
authors.initials: BE
authors.lastname: Balbo
authors.affiliation: Division of Nephrology and Molecular Medicine, Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Andressa G
authors.initials: AG
authors.lastname: Amaral
authors.affiliation: Division of Nephrology and Molecular Medicine, Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Fonseca
authors.affiliation: Division of Nephrology and Molecular Medicine, Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Isac
authors.initials: I
authors.lastname: de Castro
authors.affiliation: Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Vera M
authors.initials: VM
authors.lastname: Salemi
authors.affiliation: Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Leandro E
authors.initials: LE
authors.lastname: Souza
authors.affiliation: Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Dos Santos
authors.affiliation: Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Irigoyen
authors.affiliation: Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.affiliation: Center for Translational Research in Oncology, Cancer Institute, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Roger
authors.initials: R
authors.lastname: Chammas
authors.affiliation: Division of Nephrology and Molecular Medicine, Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil; Center for Cellular and Molecular Studies and Therapy (NETCEM), University of São Paulo, São Paulo, Brazil. Electronic address: lonuchic@usp.br.
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Onuchic
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002318:Cardiovascular Diseases / Q000150:complications / Q000235:genetics*; D004195:Disease Models, Animal; D004452:Echocardiography; D005355:Fibrosis; D037502:Galectin 3 / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000209:etiology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications / Q000235:genetics*; D050396:TRPP Cation Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D037502:Galectin 3; D050396:TRPP Cation Channels; C485095:Lgals3 protein, mouse
keywords: ADPKD; Pkd1-deficiency; apoptosis; cardiac dysfunction; cardiomyopathy; galectin-3