Journal
BIOMEDICINES
Volume 10, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/biomedicines10092301
Keywords
paraoxonase-1; cardiac hypertrophy; left ventricular function; inflammation; fibrosis
Categories
Funding
- National Institutes of Health [HL-137004, R24HL114474]
- David and Helen Boone Foundation Research Fund
- University of Toledo Women and Philanthropy Genetic Analysis Instrumentation Center
- National Heart, Lung, and Blood Institute of the National Institutes of Health [F31HL160178]
- University of Toledo Medical Research Society
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This study suggests that the loss of PON-1 in a salt-sensitive hypertensive model of chronic kidney disease leads to increased cardiac inflammation and fibrosis, as well as a molecular and functional cardiac phenotype consistent with compensated left ventricular hypertrophy.
Paraoxonase-1 (PON-1) is a hydrolytic enzyme associated with HDL, contributing to its anti-inflammatory, antioxidant, and anti-atherogenic properties. Deficiencies in PON-1 activity result in oxidative stress and detrimental clinical outcomes in the context of chronic kidney disease (CKD). However, it is unclear if a decrease in PON-1 activity is mechanistically linked to adverse cardiovascular events in CKD. We investigated the hypothesis that PON-1 is cardioprotective in a Dahl salt-sensitive model of hypertensive renal disease. Experiments were performed on control Dahl salt-sensitive rats (SSMcwi, hereafter designated SS-WT rats) and mutant PON-1 rats (SS-Pon1(em1Mcwi), hereafter designated SS-PON-1 KO rats) generated using CRISPR gene editing technology. Age-matched 10-week-old SS and SS-PON-1 KO male rats were maintained on high-salt diets (8% NaCl) for five weeks to induce hypertensive renal disease. Echocardiography showed that SS-PON-1 KO rats but not SS-WT rats developed compensated left ventricular hypertrophy after only 4 weeks on the high-salt diet. RT-PCR analysis demonstrated a significant increase in the expression of genes linked to cardiac hypertrophy, inflammation, and fibrosis, as well as a significant decrease in genes essential to left ventricular function in SS-PON-1 KO rats compared to SS-WT rats. A histological examination also revealed a significant increase in cardiac fibrosis and immune cell infiltration in SS-PON-1 KO rats, consistent with their cardiac hypertrophy phenotype. Our data suggest that a loss of PON-1 in the salt-sensitive hypertensive model of CKD leads to increased cardiac inflammation and fibrosis as well as a molecular and functional cardiac phenotype consistent with compensated left ventricular hypertrophy.
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