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

• Published in: Kidney international Vol. 90; no. 3; pp. 580 - 597
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2016
• Subjects: ADPKD; Animals; apoptosis; Apoptosis - genetics; cardiac dysfunction; cardiomyopathy; Cardiovascular Diseases - complications; Cardiovascular Diseases - genetics; Disease Models, Animal; Echocardiography; Fibrosis; Galectin 3 - genetics; galectin-3; Humans; Hypertension - etiology; Kidney - metabolism; Kidney - pathology; Mice; Mice, Knockout; Myocardium - pathology; Phenotype; Pkd1-deficiency; Polycystic Kidney, Autosomal Dominant - complications; Polycystic Kidney, Autosomal Dominant - genetics; TRPP Cation Channels - genetics; TRPP Cation Channels - metabolism; apoptosis; ADPKD; cardiac dysfunction; Pkd1-deficiency; cardiomyopathy; galectin-3
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1016/j.kint.2016.04.028

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 Pkd1cond/condNestincre (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 Pkd1cond/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 Pkd1cond/cond:Nestincre;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 (Pkd1V/V; VVG+) showed that Pkd1V/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.