Abstract: SA-PO120

Transcriptomic Profiling of BTBRob/ob and eNOS-/-db/db Kidneys Sheds Light on Contrasting Morphological Phenotypes

Session Information

Category: Diabetes

  • 503 Diabetes Mellitus and Obesity: Translational

Authors

  • Ericsson, Anette E., AstraZeneca , Gothenburg, Sweden
  • Reznichenko, Anna, AstraZeneca , Gothenburg, Sweden
  • Yang, Haichun, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
  • Sanchez, José, AstraZeneca , Gothenburg, Sweden
  • William-Olsson, Lena, AstraZeneca , Gothenburg, Sweden
  • Soderberg, Magnus, AstraZeneca, Gothenburg, Sweden
  • Fogo, Agnes B., Vanderbilt University School of Medicine, Nashville, Tennessee, United States
  • Granqvist, Anna, AstraZeneca , Gothenburg, Sweden
Background

There is a need for robust and translatable pre-clinical models for diabetic nephropathy (DN). The BTBRob/ob and eNOS-/-db/db mouse models develop progressive albuminuria and morphological lesions resembling early to moderate human disease. Mesangial expansion was evident in both models, however, podocyte foot process effacement was only local and minor in BTBRob/ob but widespread in eNOS-/-db/db.

Methods

This prompted us to perform RNA sequencing of kidney cortex and isolated glomeruli with parallel analysis of blood glucose, UACR and histology. To test whether transcriptional differences underlie the histologically disparate phenotypes, we performed an unbiased as well as targeted analysis of the RNA-seq data comparing expression profiles of a panel of known glomerular cell-specific markers that included genes for podocytes (n=50), mesangial (n=53) and glomerular endothelial cells (n=19).

Results

Obesity and hyperglycemia were present (BTBRob/ob, 16.5±2.0 mM; eNOS-/-db/db 16.1±2.5 mM blood glucose) as well as significant albuminuria in both models (BTBRob/ob, 10-fold vs lean; eNOS-/-db/db, 14-fold vs lean) at 20 (BTBRob/ob) and 18 (eNOS-/-db/db) weeks age. Transcriptomic analysis revealed a set of podocyte markers exclusively modulated in eNOS-/-db/db but not BTBRob/ob (Cd80, Kirrel, Nes, Podxl, Efnb1, Actn4, Utrn), while endothelial genes Eng, Pecam1, Kdr, Ehd3, Flt1, Tek, and Emcn were modulated in BTBRob/ob only. A number of these genes were also changed in glomeruli from human DN biopsies.

Conclusion

In summary, the two models share features of DN, however the eNOS-/-db/db mouse present more pronounced glomerular injury and podocyte effacement. Identified gene signatures suggest that the phenotype in eNOS-/-db/db has a stronger component of podocyte changes whereas BTBRob/ob has a stronger endothelial component, which may explain in part some of the differences in morphology and will be the subject for further studies.

Funding

  • Commercial Support