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Kidney Week

Abstract: TH-PO493

Paraoxonase 1 Regulation of Renal Inflammation and Fibrosis in CKD

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Khalaf, Fatimah Kareem, University of Toledo, Toledo, Ohio, United States
  • Mohammed, Chrysan J., University of Toledo College of Medicine & Life Science, Toledo, Ohio, United States
  • Dube, Prabhatchandra, University of Toledo, Toledo, Ohio, United States
  • Tassavvor, Iman, University of Toledo College of Medicine and Life Sciences, Maumee, Ohio, United States
  • Kleinhenz, Andrew, University of Toledo College of Medicine and Life Sciences, Maumee, Ohio, United States
  • Lad, Apurva, University of Toledo College of Medicine and Life Sciences, Maumee, Ohio, United States
  • Gohara, Amira F., University of Toledo College of Medicine and Life Sciences, Maumee, Ohio, United States
  • Malhotra, Deepak K., University of Toledo, Toledo, Ohio, United States
  • Haller, Steven T., University of Toledo College of Medicine and Life Sciences, Maumee, Ohio, United States
  • Kennedy, David J., The University of Toledo Health Science Campus, Toledo, Ohio, United States
Background

Paraoxonase1 (PON1) is a hydrolytic lactonase enzyme which is synthesized by the liver and circulates attached to high density lipoproteins. Clinical studies have demonstrated an association between diminished PON1 and progression of CKD however whether decreased PON1 is mechanistically linked to renal disease is unknown. We tested whether absence of PON1 is mechanistically linked to progression of renal injury in a Dahl salt-sensitive model of hypertensive renal disease.

Methods

Experiments were performed on Dahl salt-sensitive rats (wild) and PON1 knock-out rats (PON1 KO). Ten week old, male rats were maintained on high salt diet (8% NaCl) for up to 5 weeks to initiate renal disease.

Results

Early mortality was observed in 5 out of 12(41.6%) Pon1 KO rats (mean time until death=33 days), while no mortality was observed in wild type rats. At 4 weeks, Pon1 KO and wild type rats developed similar degrees of hypertension however Pon1 KO demonstrated significantly decreased renal function compared to the wild type rats as assessed by FITC-Sinistrin glomerular filtration rate as well as increases in cystatin C and urinary protein excretion. Upon histological examination, kidneys from Pon1 KO rats showed significant evidence of increased renal injury compared to the wild rats as noted by increased renal fibrosis, glomerular sclerosis, and tubular ischemia. Pon1 KO rats also showed significant increases in renal inflammation vs wild type, as measured by increased recruitment of CD68 positive immune cells in the renal interstitium. Further, expression of the key inflammatory genes (Timp-1,MCP-1,IL-6,COL1A1,andTGF-β) was significantly higher in renal tissue from Pon1 KO rats compared to the wild type rats. Also, Pon1 KO rats had significantly increased renal oxidative stress demonstrated by increased renal staining of the oxidative stress marker 8-OHdG as well higher urinary excretion of 8-OHdG vs. wild type. Finally, as activation of Src kinase has been shown to act as a common integrator of multiple pro-fibrotic signals we noted that, compared to wild type rats, renal tissue from Pon1 KO showed increased activation of Src kinase

Conclusion

Our data suggest a new role for PON-1 in regulating renal inflammation and fibrosis in the setting of hypertensive renal disease

Funding

  • Other NIH Support