The University of Toledo Translation Journal of Medical Sciences 
Cardiology Abstract, Department of Medicine Research Symposium UTJMS 2023 May 05; 11(1):e1-e1 

Paraoxanase-1 Modulates Cardiotonic 
Steroid Induced Cardiac Inflammation and 
Fibrosis in Dahl Salt Sensitive Model of 
Chronic Kidney Disease 
Meghana Ranabothu1*, Amulya Marellapudi1, Ambika Sood1, Prabhatchandra Dube1, Fatimah K. 
Khalaf1, Mitra M. Patel1, Bella Z. Khaatib-Sahidi1, Armelle DeRiso1, Apurva A. Lad1, Chrysan J. 
Mohammed1, Andrew L. Kleinhenz1, Olga V. Fedorova1, Steven T. Haller, PhD1, David J. Kennedy, 
PhD1 

1Division of Cardiology, Department of Medicine, The University of Toledo, Toledo, 

OH 43614 

*Corresponding author: Meghana.Ranabothu@rockets.utoledo.edu

Published: 05 May 2023 

Objective: Cardiotonic steroids (CTS) are known ligands of the Na+/K+-ATPase (NKA) and chronic 
elevations in volume expanded conditions such as hypertension and chronic kidney disease (CKD). 
Paraoxonase-1 (PON1) is a lactonase enzyme that can hydrolyze CTS to inactive open-ring forms 
making them incapable of stimulating NKA and initiating pro-inflammatory signaling cascades. We 
hypothesized that PON-1 can attenuate the progression of cardiac inflammation in CKD via modulating 
the pathogenic pathways induced by CTS signaling using a well characterized Dahl salt-sensitive rat 
model of hypertensive renal disease and elevated CTS. 

Methods: Dahl salt-sensitive wild type, PON1 knockout, and PON1 knockout rats that were treated with 
3E9 anti-CTS monoclonal antibody were fed a high salt diet for five weeks to induce hypertensive renal 
disease and elevate CTS levels. Hematoxylin and Eosin (H&E) staining was performed on hearts to 
analyze immune cell infiltration. Real-time PCR analysis was performed for markers of inflammation 
(IL-6, IL1β, and CCL2), hypertrophy (Myh7, NPPA, and Slc8a), and fibrosis (Timp-1).  

Results: RT-PCR analysis revealed significantly increased expression of cardiac inflammatory, 
hypertrophy, and fibrotic markers in SS-PON1 KO compared to SS-WT rats after high salt feeding. 
Treatment of SS-PON-1 KO rats with 3E9 mAb significantly decreased expression of Timp-1, IL-6, 
Ccl2, IL1β, NPPA, Myh7 and Slc8a. H&E analysis of hearts revealed significantly decreased immune 
cell infiltration in SS-PON-1KO rats treated with 3E9 mAb.  

Conclusion: Our findings suggest that PON-1 via its counter-regulatory mechanism of the CTS 
signaling axis exhibits a cardioprotective role in chronic kidney disease. 

https://dx.doi.org/10.46570/utjms.vol11-2023-644 

https://dx.doi.org/10.46570/utjms.vol11-2023-644
mailto:Meghana.Ranabothu@rockets.utoledo.edu