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Polycystin 2-dependent cardio-protective mechanisms revealed by cardiac stress

  • Muscle physiology
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Abstract

Although autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of multiple kidney cysts, the most frequent cause of death in ADPKD patients is cardiovascular disease. ADPKD is linked to mutations in PKD1 or pkd2, the genes that encode for the proteins polycystin 1 and polycystin 2 (PC1 and PC2, respectively). The cardiovascular complications have been assumed to be a consequence of renal hypertension and activation of renin/angiotensin/aldosterone (RAAS) pathway. However, the expression of PC1 and PC2 in cardiac tissue suggests additional direct effects of these proteins on cardiac function. We previously reported that zebrafish lacking PC2 develop heart failure, and that heterozygous Pkd2+/− mice are hypersensitive to acute β-adrenergic receptor (βAR) stimulation. Here, we investigate the effect of cardiac stress (prolonged continuous βAR stimulus) on Pkd2+/− mice. After βAR stimulation for 7 days, wild-type (WT) mice had increased left ventricular mass and natriuretic peptide (ANP and BNP) mRNA levels. The WT mice also had upregulated levels of PC2 and chromogranin B (CGB, an upstream regulator of BNP). Conversely, Pkd2+/− mice had increased left ventricular mass, but natriuretic peptide and CGB expression levels remained constant. Reversal of the increased cardiac mass was observed in WT mice 3 days after cessation of the βAR stimulation, but not in Pkd2+/− mice. We suggest that cardiac stress leads to upregulation of the PC2-CGB-BNP signaling axis, and this pathway regulates the production of cardio-protective natriuretic peptides. The lack of a PC2-dependent cardio-protective function may contribute to the severity of cardiac dysfunction in Pkd2+/− mice and in ADPKD patients.

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Acknowledgements

We thank Drs. Stefan Somlo and Yiqiang Cai (Yale University) for the PC2 antibody. We thank Lily Nguyen and Nicole Mikush for technical assistance. We acknowledge funding from the NIH to support the Yale Cell Biology Microscopy Core (5P30DK034989, OD020142). Grant support is acknowledged: a scholarship from the German National Merit Foundation (EG), a fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico - Brazil (FOL), K99DK101585 (IYK), 5P01DK057751, and P30DK090744 (BEE). Helpful discussions with Allison Brill are acknowledged.

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  1. Esther Giehl

    Present address: Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité – Universitätsmedizin Berlin, Berlin, Germany

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Yale University, 333 Cedar St, New Haven, CT, 06520, USA

    Esther Giehl, Fernanda O. Lemos, Ivana Y. Kuo & Barbara E. Ehrlich

  2. Department of Cardiology, School of Medicine, Yale University, 333 Cedar St, New Haven, CT, 06520, USA

    Yan Huang & Frank J. Giordano

  3. Department of Cellular and Molecular Physiology, School of Medicine, Yale University, 333 Cedar St, New Haven, CT, 06520, USA

    Barbara E. Ehrlich

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Contributions

EG, IYK, and BEE conceived the project. EG, FOL, and YH conducted experiments and EG, YH, and FOL analyzed data. EG and FOL wrote the first draft of the manuscript, and all authors edited the manuscript. All authors agreed to the final manuscript.

Corresponding author

Correspondence to Barbara E. Ehrlich.

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The Yale University Animal Ethics Committee (IACUC) approved the animal housing conditions and experimental procedures conducted in this study.

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The authors state that there are no competing interests.

Electronic supplementary material

Supplemental Fig. 1

Expression of Polycystin-2 (PC2) is increased after prolonged β-adrenergic stress. Western blot analysis of PC2 expression in cardiac ventricular tissue of 6 week old male WT and Pkd2+/− mice after 7 days of i.p. injection of saline (control) or isoproterenol (ISO: 10 mg/kg/day; 25 mg/kg/day or 50 mg/kg/day). Representative image of the blots. Each lane represents a different animal. (PDF 263 kb)

Supplemental Fig. 2

Echocardiographic and hemodynamic analysis of 6 weeks old male WT (white bar) and Pkd2+/− (black bar) mice after 7 days of isoproterenol (ISO; 25 mg/kg/day) or vehicle treatment. (A) Systolic interventricular septum thickness; (B) Diastolic interventricular septum thickness; (C) Systolic interventricular septum thickness to left ventricular internal diameter ratio; (D) Diastolic interventricular septum thickness to left ventricular internal diameter ratio; (E) Systolic left ventricular internal diameter; (F) Diastolic left ventricular internal diameter; (G) Systolic left ventricular volume; (H) Diastolic left ventricular volume; (I) Ejection Fraction; (J) Fractional shortening. Results are presented as the mean ± sem. *means p < 0.05. Two-way ANOVA, Tukey post test. (PDF 78 kb)

Supplemental Fig. 3

WT and Pkd2+/− mice have comparable enhance of contraction force in dobutamine test. Hemodynamic analysis of rate of rise of left ventricular (LV) pressure during systole in 6 weeks old male WT and Pkd2+/− mice after 7 days of isoproterenol (ISO; 25 mg/kg/day) or vehicle treatment. Results are presented as the mean ± sem. **** means p < 0.001. Two-way ANOVA, Tukey post test. (PDF 33 kb)

Supplemental Table 1

Body weights after 3 days of rest following ISO treatment. Body weight (g) of WT and Pkd2+/− mice directly after 7 days of control (saline) or stress (isoproterenol (ISO; 25 mg/kg/day)) treatment (day 7) followed by 3 days of rest (day 10). (PDF 26 kb)

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Giehl, E., Lemos, F.O., Huang, Y. et al. Polycystin 2-dependent cardio-protective mechanisms revealed by cardiac stress. Pflugers Arch - Eur J Physiol 469, 1507–1517 (2017). https://doi.org/10.1007/s00424-017-2042-7

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