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Kidney Week

Abstract: TH-PO417

Assessing Formoterol Treatment in a Mouse Model of Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Winkler, Brennan, Medical University of South Carolina, Charleston, South Carolina, United States
  • Fedoriuk, Mykhailo, Medical University of South Carolina, Charleston, South Carolina, United States
  • Zuo, Xiaofeng, Medical University of South Carolina, Charleston, South Carolina, United States
  • Deng, Peifeng, Medical University of South Carolina, Charleston, South Carolina, United States
  • Fitzgibbon, Wayne R., Medical University of South Carolina, Charleston, South Carolina, United States
  • Palygin, Oleg, Medical University of South Carolina, Charleston, South Carolina, United States
  • Lipschutz, Joshua H., Medical University of South Carolina, Charleston, South Carolina, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD) is a disease caused by mutations in the genes PKD1 and PKD2 that results in cyst growth within the kidney and over time leads to renal failure. Tolvaptan is currently the only drug approved for treating ADPKD, but it is only modestly effective and has significant side effects. ADPKD is associated with metabolic dysfunction. Treating the metabolic dysfunction in ADPKD may be therapeutic. A metabolic modulator, formoterol, is a beta-2 adrenergic receptor agonist commonly prescribed for chronic obstructive pulmonary disease. Our previous research has demonstrated the effectiveness of formoterol in treating some forms of chronic kidney disease (CKD). Metabolic dysfunction is thought to be corrected by formoterol’s ability to stimulate mitochondrial biogenesis. We hypothesize that formoterol treatment in a mouse model of ADPKD will be therapeutic in reversing, stopping, or slowing disease progression.

Methods

RC/RC mice, a model of ADPKD generated using mutations in PKD1 from a human family, will be treated using osmotic mini pumps filled with formoterol for six months at 1 mg/kg body weight/day after they reach the age of three months. Pumps will be exchanged 4-6 times over the course of treatment with blood and urine collections at each surgery for further analysis. Cohorts of 12 males and 12 females will be treated to address any sex differences in treatment; 6 mice treated and 6 mice untreated/receiving vehicle (DMSO) in each cohort. Mice will be weighed weekly. MRIs will be performed at three months and at end of the experiment on a representative sample of the mice to assess cyst burden. After six months of treatment the mice will be sacrificed, and the kidney, liver, heart, and spleen will be harvested for histological, protein, and nucleic acid-based analyses. Formoterol will also be tested in the PCK rat model of PKD.

Results


Mice
Males: To date, a trend toward lower kidney/body weight (p=0.28) and liver/body weight (p=0.07) ratios is observed in the formoterol-treated compared to the vehicle-treated mice, which may indicate decreased cystogenesis.
Females: In progress.
Rats
In progress.

Conclusion

Preliminary data suggest that formoterol may have an effect on cyst growth, though additional cohorts of treated and untreated mice need to be studied.

Funding

  • Veterans Affairs Support