Abstract: TH-PO508
Pemafibrate Exerts Renoprotective Effects by Activation of PPARα in Murine Kidneys
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
- Aomura, Daiki, Shinshu University School of Medicine, Matsumoto, Japan
- Kamijo, Yuji, Shinshu University School of Medicine, Matsumoto, Japan
Background
Recently, free fatty acid (FFA) toxicity accompanying proteinuria was identified as a main cause of tubular damage, which was aggravated by an insufficiency of peroxisome proliferator-activated receptorα (PPARα). We have reported that strongly PPARα agonistic fibrate drugs exert renoprotective effects by PPARα activation in proximal tubular epithelial cells with FFA-overload nephropathy (FAON) tubular injury model mice. In the clinical setting, however, there have been no safe PPARα agonists for patients with chronic kidney disease (CKD) since fibrate drugs have severe dose-related adverse effects, including a decrease in kidney function. Pemafibrate (PMF) was approved in Japan in 2018 as the first selective PPARα modulator (SPPARMα). PMF has much more potent and specific PPARα-activating efficacy as compared with other fibrates and is excreted in the bile. Thus, the drug can achieve greater improvements in fatty acid metabolism with a highly reduced risk of diminished kidney function and other adverse effects. Although PMF can be safely prescribed for CKD patients, it is uncertain whether it activates PPARα in the kidneys or has renoprotective effects.
Methods
We examined the above possibilities using the kidneys of wild type mice and FAON model mice with and without 0.25 mg/kg/day PMF administration for 14 days.
Results
PPARα target gene expression in the kidneys was significantly decreased in FAON model mice and it was improved by PMF treatment. The PMF treated animals also exhibited decreased levels of tubular injury, urinary protein excretion, oxidative stress (OS), and pro-inflammatory apoptosis-stimulating responses, as well as stable fatty acid metabolism. Moreover, expression of the PPARα gene and its target mRNA-encoding proteins involved in OS, pro-inflammatory responses, apoptosis, and fatty acid metabolism were maintained with PMF treatment.
Conclusion
This study’s results suggest that PMF activates renal PPARα, increases PPARα signaling, and imparts renoprotective effects.