Kidney Week

Abstract: FR-PO717

Metformin Improves Relevant Disease Parameters in the Hypomorphic Pkd1^RC/RC ADPKD Mouse Model

Session Information

• Cystic Kidney Diseases: Clinical/Translational
  November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Hallows, Kenneth R., University of Southern California, Los Angeles, California, United States

Kenneth R. Hallows,

• Li, Hui, University of Southern California, Los Angeles, California, United States

Hui Li,

• Ho, Pei-Yin, University of Southern California, Los Angeles, California, United States

Pei-Yin Ho,

• Rivera, Daniel, University of Southern California, Los Angeles, California, United States

Daniel Rivera,

• Saitta, Biagio, University of Southern California, Los Angeles, California, United States

Biagio Saitta,

• Pastor-Soler, Nuria M., University of Southern California, Los Angeles, California, United States

Nuria M. Pastor-Soler,

Group or Team Name

• Department of Medicine, Division of Nephrology and Hypertension, USC/UKRO KIdney Research Center

Background

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 or PKD2, presents with progressive development of renal cysts and eventual end-stage kidney disease and has limited treatment options. Previous work showed that metformin treatment reduces cyst growth in two early, rapid ADPKD mouse models, potentially through inhibition of CFTR-mediated fluid secretion, mTOR signaling and cAMP production. Here we tested whether metformin treatment ameliorated ADPKD manifestations in a relevant, slowly progressive ADPKD mouse model.

Methods

Using the slowly developing ADPKD mouse model with an R3277C knock-in point mutation in both alleles of the Pkd1 gene (Pkd1^RC/RC mice), male and female mice were treated ± metformin (300 mg/kg/day in drinking water) from 3 months through 9-12 months of age. During this treatment period, we periodically measured tail cuff blood pressures, glomerular filtration rates (GFR) by the FITC-sinistrin technique, and blood studies by i-Stat. At euthanasia, we assessed kidney histology (e.g., cystic index), total kidney weight/body weight ratio (TKW/BW), and mRNA and protein expression by qPCR and immunoblotting of key cell signaling, injury and inflammatory markers.

Results

As previously reported, Pkd1^RC/RC females had a more severe disease phenotype as compared with males. Metformin treatment reduced TKW/BW relative to age- and sex-matched controls at both 9 and 12 months of age. Metformin treatment also improved systolic blood pressures and increased GFR relative to controls at 9 months in both sexes. Moreover, metformin improved anemia (increased hematocrit) at both 9 and 12 months of age and generally lowered blood urea nitrogen (BUN) levels relative to controls in both sexes. Finally, metformin treatment also reduced the gene expression of key kidney injury markers, kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), and the inflammation markers tumor necrosis factor-α and interleukin-6 in these mice, along with KIM-1 protein expression.

Conclusion

Metformin improves various key ADPKD disease parameters in a relevant, slowly progressive ADPKD model. Additional studies to examine effects of metformin in PKD clinical trials and the potential additivity of these metformin effects with other mechanistically distinct ADPKD therapies are underway.

Funding

• Other U.S. Government Support