Cardioprotective Role for Paraoxonase-1 in Chronic Kidney Disease Article (Faculty180)

cited authors

  • Dube, Prabhatchandra; Khalaf, Fatimah K; DeRiso, Armelle; Mohammed, Chrysan J; Connolly, Jacob A; Battepati, Dhanushya; Lad, Apurva; Breidenbach, Joshua D; Kleinhenz, Andrew L; Khatib-Shahidi, Bella; Patel, Mitra; Tassavvor, Iman; Gohara, Amira F; Malhotra, Deepak; Morgan, Eric E; Haller, Steven T; Kennedy, David J

description

  • 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 (SS, hereafter designated SS-WT rats) and mutant PON-1 rats (SS-Pon1, 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.

authors

publication date

  • 2022

published in

volume

  • 10