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Abstract: TH-PO765

Cell Sex and Sex Hormones Modulate Kidney Glucose and Glutamine Metabolism in Health and Diabetes

Session Information

Category: Women's Health and Kidney Diseases

  • 2100 Women's Health and Kidney Diseases

Authors

  • Clotet Freixas, Sergi, Toronto General Hospital Research Institute, University Health Network,, Toronto, Ontario, Canada
  • Kotlyar, Max, Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada
  • McEvoy, Caitríona M., Toronto General Hospital Research Institute, University Health Network,, Toronto, Ontario, Canada
  • Saha, Aninda Dibya, Toronto General Hospital Research Institute, University Health Network,, Toronto, Ontario, Canada
  • Boshart, Alexander, Toronto General Hospital Research Institute, University Health Network,, Toronto, Ontario, Canada
  • Dart, Allison, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
  • Wicklow, Brandy A., Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
  • Mcgavock, Jonathan, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
  • Blydt-Hansen, Tom D., Department of Pediatrics, The University of British Columbia, Vancouver, British Columbia, Canada
  • Woo, Minna, Toronto General Hospital Research Institute, University Health Network,, Toronto, Ontario, Canada
  • Scholey, James W., Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada
  • Rost, Hannes L., The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada
  • Konvalinka, Ana, Toronto General Hospital Research Institute, University Health Network,, Toronto, Ontario, Canada
Background

Diabetic Kidney Disease (DKD) is recongnized as the leading cause of Chronic Kidney Disease (CKD). Male sex is a risk factor for CKD, and is generally associated with a more severe DKD. However, female sex renoprotection is often lost in the setting of diabetes. The molecular reasons behind the sex-specific progression of DKD, and their link to sex chromosomes and sex hormones, are unknown. Here, we identify a sex dimorphism in glucose and glutamine metabolism that is conserved in healthy and diabetic mice and humans.

Methods

We employed primary human proximal tubular epithelial cells (PTECs) from male and female donors (n=3/sex), and exposed them to sex hormones, under normal or under high glucose conditions (n=6/group). We studied male and female mice with and without gonads, as well as male and female type 1 diabetic mice (n=5-8/group). We also interrogated the serum metabolome of male and female adolescents with type 2 diabetes and their controls (n=180).

Results

Female PTECs displayed decreased glycolysis, mitochondrial respiration, oxidative stress, apoptosis, and high glucose-induced injury, compared to male PTECs. The more oxidative phenotype of male PTECs was enhanced by dihydrotestosterone (DHT) and linked to increased mitochondrial utilization of glucose and glutamine. Studies in vivo pointed towards decreased glutamine anaplerosis in diabetic female kidneys. Female PTECs displayed increased levels of pyruvate, glutamyl-cysteine, cysteinylglycine, and a higher GSH/GSSG ratio than male PTECs, indicative of enhanced redox homeostasis. Conversely, male sex was linked to increased levels of glutamate, TCA cycle, and glutathione cycle metabolites, in PTECs and in the blood metabolome of healthy youth and youth with type 2 diabetes. Finally, we identified transcriptional mechanisms that control kidney metabolism in a sex-specific fashion. While X-linked demethylase KDM6A facilitated metabolic homeostasis in female PTECs, transcription factor HNF4A mediated the deleterious effects of DHT in male PTECs.

Conclusion

This work uncovers the role of sex in renal glucose and glutamine metabolism, that may explain the roots of sex dimorphism in kidney health and DKD, and inspires new paradigms based on patient sex.