Date of Award

Spring 1-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

First Advisor

Surya Nauli

Second Advisor

Keykavous Parang

Third Advisor

Marco Bisoffi

Fourth Advisor

Jennifer Totonchy

Abstract

Background: Autosomal dominant polycystic kidney disease (PKD) is a hereditary disorder affecting multiple organs, including the heart. PKD patients have been associated with arrhythmogenic remodeling in some clinical evaluations. However, the structural changes in myocardium and pathway analyses on the pathology of human PKD hearts have never been studied.

Methods: Sex- and age-matched human heart tissues from non-PKD and PKD were studied and verified in a heart-specific PKD mouse model. Structural and functional abnormalities of cardiac tissues and fibrosis-associated pathways were analyzed.

Results: Human PKD myocardium were infiltrated by inflammatory cells M1 and M2. Expressions of transforming growth factor (TGF-β1) and TGF-β1 receptor in both human and mouse tissues were upregulated with nuclear translocation of pSMAD3 and β-catenin. The increase in extracellular matrix led to cardiac hypertrophy and fibrosis, causing cardiac dysfunctions with a predisposition to arrhythmia. Impairment in left ventricular (LV) expansion or compliance and LV filling in fibrotic PKD hearts resulted in diastolic dysfunction. LV systolic contractility and elastance decreased in fibrotic PKD hearts resulted in systolic dysfunction.

Conclusions: Hearts from PKD patients are characterized with hypertrophy and fibrosis in the interstitial, perivascular and conduction system with upregulated TGF-β1 and its receptor. Human studies are validated by the mouse PKD model, indicating systolic and diastolic dysfunctions with arrhythmogenic hearts.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Available for download on Wednesday, January 25, 2023

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