Kidney Week

Abstract: TH-OR050

Fenofibrate, a PPARA Agonist, Enhances Mitochondrial Metabolism and Slows Kidney and Liver Cyst Progression in a 6 Month Pre-Clinical Trial

Session Information

• Cystic Kidney Diseases: Genes, Mechanisms, Interventions
  November 02, 2017 | Location: Room 390, Morial Convention Center
  Abstract Time: 06:18 PM - 06:30 PM

Category: Genetic Diseases of the Kidney

• 801 Cystic Kidney Diseases

Authors

• Lakhia, Ronak, University of Texas Southwestern Medical Center, Dallas, Texas, United States

Ronak Lakhia, MD



http://profiles.utsouthwestern.edu/profile/66537/ronak-lakhia.html

• Yheskel, Matanel, University of Texas Southwestern Medical Center, Dallas, Texas, United States

Matanel Yheskel,

• Flaten, Andrea N, University of Texas Southwestern Medical Center, Dallas, Texas, United States

Andrea N Flaten,

• Quittner-Strom, Ezekiel, University of Texas Southwestern Medical Center, Dallas, Texas, United States

Ezekiel Quittner-Strom,

• Patel, Vishal, University of Texas Southwestern Medical Center, Dallas, Texas, United States

Vishal Patel,

Background

Impaired fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) are thought to underlie ADPKD progression. Peroxisome proliferator activated receptor alpha (PPARA) is a key regulator of FAO and OXPHOS. PPARA is downregulated in mouse and human ADPKD kidney cysts. We recently showed that deletion of Ppara aggravates cyst formation in an ADPKD model. The goal of this study was to determine if augmentation of FAO using the PPARA agonist fenofibrate can slow cyst growth.

Methods

Q-PCR, Western blot, and immunofluorescence staining confirmed downregulation of Ppara and its FAO-related target genes in 200-day-old Pkd1^RC/RC mice. Sixteen 50-day-old Pkd1^RC/RC mice were randomized to receive either standard chow diet or standard chow diet supplemented with fenofibrate. All mice underwent MRI to determine total kidney volume and total cyst volume at 180 days of age and were subsequently sacrificed at 200 days of age for molecular and histological analysis. An additional cohort of mice underwent in-vivo FAO assessment by ³H-triolein assay.

Results

Fenofibrate treatment upregulated PPARA and enhanced FAO and OXPHOS in the kidneys of Pkd1^RC/RC mice as evidenced by upregulation of FAO/OXPHOS genes, improved mitochondrial biogenesis, and increased oxidation of ³H-triolein. MRI-assessed total kidney volume and total cyst volume was reduced by 30% and 60%, respectively, in fenofibrate-treated Pkd1^RC/RC mice compared to Pkd1^RC/RC mice on control diet. Moreover, kidney-weight-to-body-weight ratio, cyst index and serum creatinine were also reduced in the fenofibrate-treated Pkd1^RC/RC mice. Fenofibrate treatment was associated with reduced kidney cyst proliferation and M2-like macrophages infiltration in Pkd1^RC/RC mice treated with fenofibrate compared to Pkd1^RC/RC mice on control diet. Fenofibrate treatment also reduced liver cyst burden, cyst proliferation, and liver inflammation and fibrosis.

Conclusion

Fenofibrate augments Ppara expression, improves FAO, and slows kidney and liver cyst growth, in Pkd1^RC/RC mice. Our studies suggest that normalizing Ppara activity may be a useful therapeutic strategy for ADPKD.

Funding

• NIDDK Support