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Abstract: TH-PO688

Effects of Pharmacologic Galectin-3 Inhibition on the Cardiac Phenotype and Survival of Pkd1-Deficient Mice

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Amaral, Andressa G., University of São Paulo, São Paulo, Brazil
  • Freitas, Jessica A., University of São Paulo, São Paulo, Brazil
  • Melo, Marcelo D., University of São Paulo, São Paulo, Brazil
  • Salemi, Vera Mc, University of São Paulo, São Paulo, Brazil
  • Onuchic, Luiz F., University of São Paulo, São Paulo, Brazil

Myocardial abnormalities are a significant phenotype in ADPKD. We have previously shown that Pkd1-deficient mice develop cardiac dysfunction, a phenotype significantly rescued by galectin-3 (Gal-3) knockout.


In this scenario, we investigated the effects of 2 Gal-3 inhibitors on the cardiac phenotype of a Pkd1+/- noncystic mouse (HT) and on survival of a severely cystic mouse homozygous for a Pkd1-knockin allele that prevents polycystin-1 cleavage (VV). GR-MD-02 (GR, 60mg/kg), a Gal-3 extracellular inhibitor, or FTS (10mg/kg), an intracellular inhibitor of Gal-3/Ras interaction, was administered intraperitoneally 3x/week, starting at P1. Echocardiographic and protein expression analyses were performed in HT and wild-type (WT) mice at 5-6 weeks while survival was assessed in VVs.


Left ventricular (LV) ejection fraction and shortening fraction were decreased in HTs compared to WTs [43.1% (35.8-54.2) vs 59.2% (52.8-66.0), p<0.01; and 23.3% (22.9-25.1) vs 31.2% (25.2-39.4), p<0.01; respectively], parameters partially rescued by FTS [52.3% (48.8-57.1) and 27.0% (22.5-29.3) vs untreated WT, NS], but not by GR. Interventricular septum diameter, on the other hand, was increased by GR in HTs [0.75 (0.71-0.81) vs 0.63mm (0.55-0.68), p<0.01), with only a trend for FTS (p=0.09). GR was also followed by trends of increase in LV mass/BW (p=0.12) and LV posterior wall diameter (p=0.08) in HTs. GR increased P-ERK2 expression in HT and WT hearts [1.70 (1.19-2.46) vs 1.29 AU (0.82-1.32), p<0.05; and 1.65 (1.03-3.49) vs 1.01 AU (0.94-1.07), p<0.05; respectively], while FTS increased P-ERK2 only in WTs [1.98 AU (1.52-2.51), p<0.01]. GR and FTS did not modify expression of P-GSK3β and P-PKCα and δ in HT and WT hearts, and did not improve survival in VVs.


Our findings revealed that intracellular inhibition of Gal-3 partially rescued systolic function parameters in HTs while its extracellular inhibition induced cardiac hypertrophy without rescuing the systolic phenotype. Differences between effects of pharmacologic inhibition and genetic Gal-3 KO are likely based on their distinct timings of Gal-3 activity suppression, levels of suppression and action site profiles. Our data suggest that pharmacologic Gal-3 inhibition may lead to beneficial effects on the ADPKD cardiac phenotype under specific circumstances.


  • Government Support - Non-U.S.