Kidney Week

Abstract: FR-PO688

Farnesoid X Receptor Agonist Obeticholic Acid Reduces Kidney Disease in a Mouse Model of Alport Syndrome

Session Information

• Glomerular Diseases: Podocyte Biology - I
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1304 Glomerular Diseases: Podocyte Biology

Authors

• Jones, Bryce A., Georgetown University Medical Center, Washington, District of Columbia, United States

Bryce A. Jones,

• Perry, Priscilla E., Georgetown University Medical Center, Washington, District of Columbia, United States

Priscilla E. Perry,

• Davidson, Shania Ro'Shea, Georgetown University Medical Center, Washington, District of Columbia, United States

Shania Ro'Shea Davidson,

• Lopez Santiago, Isabel, Georgetown University Medical Center, Washington, District of Columbia, United States

Isabel Lopez Santiago,

• Adapa, Sharmila, Georgetown University Medical Center, Washington, District of Columbia, United States

Sharmila Adapa,

• Allen, Katherine C., Georgetown University Medical Center, Washington, District of Columbia, United States

Katherine C. Allen,

• Dial, Katelyn, Georgetown University Medical Center, Washington, District of Columbia, United States

Katelyn Dial,

• Rowland, Emma, Georgetown University Medical Center, Washington, District of Columbia, United States

Emma Rowland,

• Myakala, Komuraiah, Georgetown University Medical Center, Washington, District of Columbia, United States

Komuraiah Myakala,

• Wang, Xiaoxin, Georgetown University Medical Center, Washington, District of Columbia, United States

Xiaoxin Wang,

• Levi, Moshe, Georgetown University Medical Center, Washington, District of Columbia, United States

Moshe Levi,

Background

Alport syndrome is a rare hereditary kidney disease caused by a mutation in the collagen IV α3α4α5 heterotrimer. The farnesoid X receptor (FXR) is a nuclear hormone receptor that is activate by bile acids. FXR agonism has been shown to protect the kidney in preclinical models of kidney disease, but no study thus far has investigated FXR agonism in an orphan kidney disease. Obeticholic acid is an FXR agonist approved for clinical use, and this greatly increases the translational value of preclinical studies with OCA. In this study, we test the hypothesis that obeticholic acid protects the kidney in a mouse model of Alport syndrome.

Methods

Male Col4a3^tm1Jhm mice on 129S1/SvImJ were fed control diet (PicoLab 5053) alone or admixed with OCA (30 mg/kg BW) between 3 and 10 weeks of age. Col4a3^-/- mice were the diseased mice, and Col4a3^+/- and Col4a3^+/+ were the control mice. Plasma, urine, and organs were harvested at time of euthanasia for biochemical analyses.

Results

As expected, vehicle-treated Col4a3^-/- mice had increase blood urea nitrogen (P < .0001), plasma creatinine (P < .0001), and urinary albumin-to-creatinine ratio (P < .0001) compared to control mice. Compared to vehicle-treated Col4a3^-/- mice, OCA-treated Col4a3^-/- mice had lower blood urea nitrogen (P < .05), plasma creatinine (trend, P < .06), and urinary albumin-to-creatinine ratio (P < .05) compared to vehicle-treated Col4a3^-/- mice. Immunostaining for fibronectin and polarized imaging of picrosirius red (PSR) stained kidneys showed that OCA treatment prevented renal fibrosis compared to vehicle-treated mice (P < .05).

Conclusion

Obeticholic acid reduces kidney disease in a mouse model of Alport syndrome. Reduced renal fibronectin and PSR-positive staining suggests an OCA-mediated antifibrotic mechanism underlies at least part of the observed benefit.

Funding

• NIDDK Support