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Hypertrophic and fibrotic human PKD hearts are associated with macrophage infiltration and abnormal TGF-β1 signaling

Cell and Tissue Research volume 391, pages 189–203 (2023)Cite this article

Abstract

Autosomal dominant polycystic kidney disease (PKD) is a hereditary kidney disorder which can affect cardiovascular system. Cardiac hypertrophy and cardiomyopathy in PKD have been reported by echocardiography analyses, but histopathology analyses of human PKD hearts have never been examined. The current studies evaluated human heart tissues from five subjects without PKD (non-PKD) and five subjects with PKD. Our histopathology data of human PKD hearts showed an increased extracellular matrix associated with cardiac hypertrophy and fibrosis. Hypertrophy- and fibrosis-associated pathways involving abnormal cardiac structure were next analyzed. We found that human PKD myocardium was infiltrated by inflammatory macrophage M1 and M2; expression of transforming growth factor (TGF-β1) and its receptor were upregulated with overexpression of pSmad3 and β-catenin. Because patients with PKD have an abnormal kidney function that could potentially affect heart structure, we used a heart-specific PKD mouse model to validate that cardiac hypertrophy and fibrosis were independent from polycystic kidney. In summary, our data show that hearts from human PKD were characterized by hypertrophy, interstitial fibrosis, perivascular fibrosis, and conduction system fibrosis with upregulated TGF-β1 and its receptor. We suggest that such structural abnormalities may predispose to systolic and diastolic cardiac dysfunction in the PKD myocardium.

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Availability of data and materials

The data that support the findings of this study are available from the corresponding author on reasonable request. Some data and samples may not be made available because of privacy or ethical restrictions.

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Acknowledgements

Jefferey Kim and Delia Tifrea assisted FA and RAE in the procurement and processing of human heart samples at UC Irvine. Denisse Larin-Henriquez assisted FA in reagent preparation and chemical ordering at Chapman University. The authors also acknowledge the support of the Chao Family Comprehensive Cancer Center Experimental Tissue Shared Resource, supported by the National Cancer Institute of the National Institutes of Health under award number P30CA062203.

Funding

This work was supported in part by the NIH HL147311 and HL147311-S1.

Author information

Authors and Affiliations

  1. Department of Biomedical and Pharmaceutical Sciences, Chapman University, 9401 Jeronimo Road, Irvine, CA, 92618-1908, USA

    Farideh Amirrad & Surya M. Nauli

  2. Department of Medicine, University of California Irvine, Orange, CA, 92868, USA

    Farideh Amirrad & Surya M. Nauli

  3. Department of Anatomic Pathology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA

    Gregory A. Fishbein

  4. Department of Pathology and Lab Medicine, University of California Irvine, Orange, CA, 92868, USA

    Robert A. Edwards

Authors
  1. Farideh Amirrad
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  2. Gregory A. Fishbein
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  3. Robert A. Edwards
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  4. Surya M. Nauli
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Contributions

FA collected and analyzed data, drafted the manuscript, oversaw the experimental progress, and served as a double-blind operator. GAF and RAE collected and assisted in procuring and processing human tissue samples. SMN drafted the manuscript and served as a double-blind operator. All authors participated in finalizing the manuscript.

Corresponding author

Correspondence to Surya M. Nauli.

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Ethics approval and consent to participate

The human-subjects research project was approved by and per accordance with the Chapman University Institutional Review Board (IRB# 1415H040 and FWA#00011020). The approval for tissue procurement was extended to each respective site identified in our IRB application. All retrospective samples from deceased subjects had been previously de-identified by the Department of Pathology and Laboratory Medicine at the UC Los Angeles and UC Irvine.

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The authors declare no competing interests.

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Significance Statement

• Histopathology analyses of PKD patients’ hearts show an increase in extracellular matrix associated with cardiac hypertrophy and fibrosis.

• Hypertrophy- and fibrosis-associated pathways are upregulated in human PKD hearts.

• Human PKD hearts are grossly infiltrated by inflammatory macrophage M1 and M2.

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Supplementary file1 (PDF 1491 KB)

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Amirrad, F., Fishbein, G.A., Edwards, R.A. et al. Hypertrophic and fibrotic human PKD hearts are associated with macrophage infiltration and abnormal TGF-β1 signaling. Cell Tissue Res 391, 189–203 (2023). https://doi.org/10.1007/s00441-022-03704-y

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  • DOI: https://doi.org/10.1007/s00441-022-03704-y

Keywords

  • Kidney disorder
  • Fibrosis
  • Hypertrophy