High resolution molecular and histological analysis of renal disease progression in ZSF1 fa/faCP rats, a model of type 2 diabetic nephropathy

PLoS One. 2017 Jul 26;12(7):e0181861. doi: 10.1371/journal.pone.0181861. eCollection 2017.

Abstract

ZSF1 rats exhibit spontaneous nephropathy secondary to obesity, hypertension, and diabetes, and have gained interest as a model system with potentially high translational value to progressive human disease. To thoroughly characterize this model, and to better understand how closely it recapitulates human disease, we performed a high resolution longitudinal analysis of renal disease progression in ZSF1 rats spanning from early disease to end stage renal disease. Analyses included metabolic endpoints, renal histology and ultrastructure, evaluation of a urinary biomarker of fibrosis, and transcriptome analysis of glomerular-enriched tissue over the course of disease. Our findings support the translational value of the ZSF1 rat model, and are provided here to assist researchers in the determination of the model's suitability for testing a particular mechanism of interest, the design of therapeutic intervention studies, and the identification of new targets and biomarkers for type 2 diabetic nephropathy.

MeSH terms

  • Animals
  • Cluster Analysis
  • Collagen / genetics
  • Collagen / metabolism
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetic Nephropathies / etiology
  • Diabetic Nephropathies / genetics*
  • Diabetic Nephropathies / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Gene Expression Profiling / methods
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Immunohistochemistry
  • Kidney / metabolism*
  • Kidney / pathology
  • Kidney / ultrastructure
  • Kidney Failure, Chronic / complications*
  • Kidney Failure, Chronic / pathology
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / ultrastructure
  • Male
  • Microscopy, Electron, Transmission
  • Obesity / complications
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Collagen

Grants and funding

KD, SZ, FJS, LS, GC, BGJ, LX, VN, YZ, MPL, JW, QN, GB, TPB, BZ, BLH, and RVM are employed by the commercial entity Pfizer Worldwide Research and Development. MAK and FG are employed by the commercial entity Nordic Bioscience A/S. The funders provided support in the form of salaries for authors but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.