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Kidney Week

Abstract: FR-PO726

Anti-Polyamine Therapy Restrains Polycystic Kidney Disease in Orthologous Mice

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Fields, Timothy A., Univ of Kansas Med Ctr, Kansas City, Kansas, United States
  • Vitek, Michael P., Resilio Therapeutics LLC, Durham, North Carolina, United States
  • Swenson-Fields, Katherine, Univ of Kansas Med Ctr, Kansas City, Kansas, United States

Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2 and is characterized by cysts derived from renal tubules. Cysts slowly expand due to aberrant proliferation and secretion of cyst-lining epithelial cells, ultimately destroying the kidney by compression and resulting fibrosis. Only one FDA-approved drug is available for ADPKD, so there is a critical need for new therapies for this disease.
The polyamines are metabolites of the amino acid ornithine and are produced by all cells. These metabolites are involved in a large number of cellular processes, including proliferation, for which they are essential. Polyamine production is often elevated in proliferative diseases, including multiple types of cancer, and inhibition of polyamine synthesis has been shown in some cases to restrain cancer progression.
We hypothesized that polyamines promote cyst cell proliferation and disease progression in ADPKD. We tested this by treating an ADPKD-orthologous mouse model with DiFluoroMethylOrnithine (DFMO), an inhibitor of the rate-limiting enzyme (ornithine decarboxylase) responsible for polyamine biosynthesis.


Pkd1RC/RC mice (“RC”), which have a missense mutation [Pkd1(p.R3277C)] that matches an allele found in a human ADPKD family, were used. RC mice were given DFMO in the drinking water (665 mg/l) to achieve a dose of 133 mg/kg starting at PN28. Mice were sacrificed at 6 mo, and serum and kidneys were collected for assessment of 2 kidney/body weight (2K/BW), cystic index, fibrosis, proliferation, apoptosis, and BUN. RNA was collected from kidneys in control, DFMO-treated, and wild-type (C57Bl/6 at 6 month) mice for expression profiling by RNA-Seq.


DFMO treatment had no effect on overall body weight but significantly lowered 2K/TBW and cystic index. There was no effect on BUN, which does not become elevated in RC mice until ~9 months. Assessments of other disease parameters are in progress. RNA-Seq analysis indicates inhibitory effects of DFMO on c-Myc and mTOR, as well as inflammatory pathways.


Inhibition of polyamine production by DFMO restrains kidney growth and cyst expansion in an orthologous model of ADPKD, potentially through effects on c-Myc and mTOR+1187 pathways. These data suggest that DFMO, which has been approved for use in humans, is a potential therapy for ADPKD.


  • NIDDK Support