Abstract: TH-PO688

Proteomics and Systems Biology Analysis of Human Kidney Cells Reveals a Link between Androgen-Induced Alterations in Renal Metabolism and Circulating Metabolite Levels in CKD

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Clotet freixas, Sergi, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
  • Konvalinka, Ana, Mount Sinai Hospital, Toronto, Canada, Toronto, Ontario, Canada
  • Soler, Maria Jose, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
  • Riera, Marta, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
  • Pascual, Julio, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
  • Batruch, Ihor, Mount Sinai Hospital, Toronto, Canada, Toronto, Ontario, Canada
  • Vasiliou, Stella K., Mount Sinai Hospital, Toronto, Canada, Toronto, Ontario, Canada
  • Dimitromanolakis, Apostolos, Mount Sinai Hospital, Toronto, Canada, Toronto, Ontario, Canada
  • Diamandis, Eleftherios P., Mount Sinai Hospital, Toronto, Canada, Toronto, Ontario, Canada
  • Scholey, James W., University Health Network, University of Toronto, Toronto, Ontario, Canada
Background

Male sex predisposes to chronic kidney disease (CKD) progression. We hypothesized that dihydrotestosterone (DHT) would affect renal cells by altering the proteome.

Methods

We used isotope labeling to quantify the proteome in human proximal tubular epithelial cells (PTEC) exposed to DHT or estradiol. Top proteins were verified in vitro and in vivo. Renal oxidative stress (OS) was assessed by N-Tyr staining. Systems biology of sex hormone-protein signatures was studied in Cytoscape.

Results

Of 5043 quantified proteins, 76 were regulated by sex hormones. Processes related to metabolism were significantly enriched in proteins regulated by DHT. Proteins representing glucose, glucosamine and fatty acid metabolism, namely glucose-P-isomerase (GPI), glucosamine-P-N-acetyltransferase (GNPNAT1), and mitochondrial trifunctional protein subunit alpha(HADHA), were validated in vitro and in vivo. Renal expression of GPI, GNPNAT1 and HADHA was significantly higher in males compared to females, in 2 models of diabetes. OS was enriched in our proteins and genes highly expressed in diabetic kidneys. We demonstrated increased OS in diabetic and control male mice kidneys. We asked whether dysregulated metabolic enzymes in male kidneys may be responsible for changes in circulating metabolites. Using data from the human KORA F4 study, we found that serum metabolites related to TCA cycle and aminoacid metabolism (e.g.malate, glutamine and proline) were increased in CKD men and also associated with our DHT-proteins.

Conclusion

Androgen-induced perturbations in renal metabolism may be responsible for the more rapid kidney disease progression ascribed to men. Metabolic alterations in the male kidney may be reflected in circulating levels of malate, glutamine, and proline metabolites in CKD.