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Abstract: FR-PO555

Dynamics of the Renal Transcriptomic Profile Through the Course of the Disease in Experimental ADPKD

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Alsawaf, Yahya, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Trask, Cassandra, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Kazeminia, Sara, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Eirin, Alfonso, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Irazabal, Maria V., Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD) is a chronic disease spanning an affected individual’s life where earlier stages are marked by cyst development and kidney enlargement with preservation of renal function and later stages by increased kidney fibrosis and renal function decline. To understand the underlying molecular processes accompanying the dynamics of the disease phenotype, we comprehensively characterized the kidney transcriptomic profile in the slowly progressive hypomorphic Pkd1 mutant mouse (p.Arg3277Cys, Pkd1RC/RC) across the course of the disease.

Methods

Pkd1RC/RC and wild type (WT) mice (n=10, 5 males and 5 females each) were studied longitudinally, and their renal mRNA profiles were analyzed using high-throughput mRNA-sequencing (seq) at 1, 6, and 12m (n=5 each). Disease severity and progression were evaluated by kidney weight/body weight (KW/BW), cystic index (CI), fibrotic index (FI), and BUN. Renal tubular cell proliferation, inflammation, mitochondrial morphology, and metabolic function were assessed by immunostaining, western blot, electron microscopy, and metabolomics at all time points.

Results

KW/BW and CI were higher in Pkd1RC/RC from 1m and FI from 6m, but BUN was similar until 12m. mRNA-seq identified an important number of differentially expressed (DE) genes [fold-change ≥ 2, and false discovery rate (FDR) ≤ 0.05] in Pkd1RC/RC versus WT kidneys, which was higher at 1- compared to 6-, but further increased at 12m (Figure). Functional analysis showed that while DE genes were primarily implicated in inflammation, immune response, and mitochondrial functions, different signatures characterize each timepoint. Confirmatory studies on cell proliferation, inflammation, mitochondria, and kidney metabolism agreed.

Conclusion

Our findings that the renal phenotype and transcriptomic landscape varied across the course of ADPKD may have significant clinical implications and suggest that different therapeutic strategies might be beneficial throughout the disease.

Funding

  • NIDDK Support