Abstract: TH-PO378

Sexual Dimorphic Response of Murine Kidneys to Dietary Cadmium and Fat

Session Information

Category: Cell Biology

  • 201 Cell Signaling, Oxidative Stress

Authors

  • Jacobs, Mitchell A, University of Louisville, School of Medicine, Louisville, Kentucky, United States
  • Merchant, Michael, University of Louisville, School of Medicine, Louisville, Kentucky, United States
  • Barati, Michelle T., University of Louisville, School of Medicine, Louisville, Kentucky, United States
  • Rane, Madhavi J., University of Louisville, School of Medicine, Louisville, Kentucky, United States
  • Gaweda, Adam E., University of Louisville, School of Medicine, Louisville, Kentucky, United States
  • Jacobs, Alfred A., University of Louisville, School of Medicine, Louisville, Kentucky, United States
  • Klein, Jon B., University of Louisville, School of Medicine, Louisville, Kentucky, United States
  • Arteel, Gavin E., University of Louisville, School of Medicine, Louisville, Kentucky, United States
  • Freedman, Jonathan H, University of Louisville, School of Medicine, Louisville, Kentucky, United States
  • Cai, Lu, University of Louisville, School of Medicine, Louisville, Kentucky, United States
Background

Obesity and cadmium (Cd) are associated with CKD. This study examined the longer-term effects of heavy metal exposure and high dietary fat on kidneys of male and female mice.

Methods

C57B/6J mice were maintained/bred on normal or 5ppm Cd drinking water and normal chow. Offspring were maintained on identical drinking water as parents but split into male and female groups fed low fat or high fat (42% saturated fat) diets. Upon sacrifice (10wks) tissue was collected for histochemical and biochemical analysis. Tissue Cd levels were measured by ICP-MS. Cortical tissue phosphoproteome was studied using LCMS-based proteomics. Phosphopeptide data were compared using GO annotation, kinase motif enrichment (Motif-x, Phosphosite), fuzzy-c means clustering, protein-protein interaction (PPI) networks (StringDB) and Ingenuity Pathways Analysis (IPA).

Results

At 10wks, no gross effects of diet or Cd were observed in female kidneys. In contrast, Cd exposed male kidneys demonstrated cortical tubular vacuolization. Kidney wet weight was higher in males by diet or Cd. Cd levels (ngCd/g kidney) were significantly higher in females and high fat increased female Cd levels almost two fold. By LCMS 1,787 unique phosphopeptides were detected, including 14 unique kinase phosphorylation motifs. Clustering and GO analysis suggested high-fat and Cd effected FGF- & EGF-signaling in both sexes. PPI analyses identified effected molecular signaling pathways for gene transcription, protein translation, and cytoskeletal/cell junction maintenance. IPA identified the insulin signaling pathway as the most significantly affected pathway.

Conclusion

Cd and/or HFD affects the insulin signaling suggesting that these environmental factors may be contributors to diabetic CKD. The renal response to 5ppm Cd and/or a high fat diet suggests strong sexual dimorphism at the tissue and molecular signaling levels.

Funding

  • NIDDK Support