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Kidney Week

Abstract: PO0938

Cell Sex and Sex Hormones Modulate Glucose and Glutamine Kidney Metabolism: Implications for Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Clotet Freixas, Sergi, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
  • Van, Julie Anh Dung, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
  • McEvoy, Caitriona M., Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
  • Farkona, Sofia, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
  • Mehrotra, Aman, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
  • Gehring, Adam J., Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
  • Woo, Minna, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
  • Konvalinka, Ana, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Background

Male sex predisposes to diabetic kidney disease (DKD). We uncovered androgen-induced perturbations in kidney metabolic proteins that may drive faster DKD progression in men. Our goal is to characterize cell sex- and sex hormone-specific alterations in the kidney cell metabolism.

Methods

Human primary proximal tubule epithelial cells (PTEC) from 3 male and 3 female donors were stimulated with control, dihydrotestosterone (DHT), or estradiol (EST). We assessed glycolysis (extracellular acidification rate, ECAR) and oxygen consumption rate (OCR) in a Seahorse analyzer. We also studied sex differences in 16-week-old diabetic Akita mice.

Results

Male PTEC showed significantly higher ECAR, OCR, superoxide levels and apoptosis, compared to female PTEC (p<0.05). Higher OCR in male PTEC was further enhanced in the presence of glutamine as a unique susbstrate. In male PTEC, ECAR was increased by DHT, whereas OCR was increased by DHT and EST. Further, glucose levels in the media were reduced by DHT. DHT-induced metabolic changes were prevented by androgen receptor (AR) inhibitors. ATP, superoxide and apoptosis were increased by DHT, especially in male PTEC. Under hyperglycemia (25mM glucose), male cells showed a more rapid decline in OCR, and DHT increased superoxide and ATP levels. Transcriptional regulator analysis predicted that PTBP1, MCM4, and KDM5D (Y-linked) regulate proteins increased by DHT. Targets of PTBP1 and MCM4 include enzymes involved in glucose and glutamine metabolism (TKT, GLUD1). In vivo, diabetes increased kidney gene expression of Tkt, Glud1, and glutamine transporter Slc38a3 in males, but not females.

Conclusion

PTEC metabolism is influenced by cell sex and sex hormones. Male PTEC show higher glycolysis, oxygen consumption, and respiratory capacity than female PTEC, and a higher propensity to oxidize glutamine in the mitochondria. Importantly, glutamine plays a key role as anaplerotic substrate for the TCA cycle in diabetes. Our in vivo data support the link between male sex and regulation of glutamine metabolism, and suggests that kidney utilization of glutamine in DKD is sex-specific. By understanding and monitoring how these metabolic changes occur in male and female patients, our findings may contribute to a more personalized management of DKD.