Paraoxonase-1 Regulation of Renal Inflammation and Fibrosis in Chronic Kidney Disease

• Main Authors: Fatimah K. Khalaf (Author), Chrysan J. Mohammed (Author), Prabhatchandra Dube (Author), Jacob A. Connolly (Author), Apurva Lad (Author), Usman M. Ashraf (Author), Joshua D. Breidenbach (Author), Robin C. Su (Author), Andrew L. Kleinhenz (Author), Deepak Malhotra (Author), Amira F. Gohara (Author), Steven T. Haller (Author), David J. Kennedy (Author)
• Format: Book
• Published: MDPI AG, 2022-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Papraoxonase-1 (PON1) is a hydrolytic lactonase enzyme that is synthesized in the liver and circulates attached to high-density lipoproteins (HDL). Clinical studies have demonstrated an association between diminished PON-1 and the progression of chronic kidney disease (CKD). However, whether decreased PON-1 is mechanistically linked to renal injury is unknown. We tested the hypothesis that the absence of PON-1 is mechanistically linked to the progression of renal inflammation and injury in CKD. Experiments were performed on control Dahl salt-sensitive rats (SS^Mcwi, hereafter designated SS rats) and Pon1 knock-out rats (designated SS-Pon1^em1Mcwi, hereafter designated SS-PON-1 KO rats) generated by injecting a CRISPR targeting the sequence into SS^Mcwi rat embryos. The resulting mutation is a 7 bp frameshift insertion in exon 4 of the PON-1 gene. First, to examine the renal protective role of PON-1 in settings of CKD, ten-week-old, age-matched male rats were maintained on a high-salt diet (8% NaCl) for up to 5 weeks to initiate the salt-sensitive hypertensive renal disease characteristic of this model. We found that SS-PON-1 KO rats demonstrated several hallmarks of increased renal injury vs. SS rats including increased renal fibrosis, sclerosis, and tubular injury. SS-PON-1 KO also demonstrated increased recruitment of immune cells in the renal interstitium, as well as increased expression of inflammatory genes compared to SS rats (all <i>p</i> < 0.05). SS-PON-1 KO rats also showed a significant (<i>p</i> < 0.05) decline in renal function and increased renal oxidative stress compared to SS rats, despite no differences in blood pressure between the two groups. These findings suggest a new role for PON-1 in regulating renal inflammation and fibrosis in the setting of chronic renal disease independent of blood pressure.

Item Description

10.3390/antiox11050900
2076-3921