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Kidney Week

Abstract: TH-PO617

Investigating the Sex-Specific Progression of CKD: Sex Hormones and Sex of the Cell in Human Kidney Metabolism

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1301 Health Maintenance, Nutrition, and Metabolism: Basic

Authors

  • Clotet-Freixas, Sergi, University Health Network, Toronto, Ontario, Canada
  • Van, Julie Anh Dung, University Health Network, Toronto, Ontario, Canada
  • Mehrotra, Aman, University Health Network, Toronto, Ontario, Canada
  • Woo, Minna, University Health Network, Toronto, Ontario, Canada
  • Caudy, Amy A., University of Toronto, Toronto, Ontario, Canada
  • Konvalinka, Ana, University Health Network, Toronto, Ontario, Canada
Background

Male sex predisposes to chronic kidney disease (CKD). We hypothesized that the effector androgen dihydrotestosterone (DHT) would induce key molecular alterations in human renal proximal tubular epithelial cells (PTECs). We quantified the proteome of DHT- vs. estradiol(EST)-treated PTECs, and uncovered androgen-induced perturbations in renal metabolism that may be directly responsible for the faster CKD progression in men. Our goal is to characterize sex- and sex hormone-specific alterations in the PTEC metabolic function, and relate them to hypertrophy, oxidative stress, and inflammation.

Methods

PTECs from 2 male vs. 2 female donors were stimulated with Control, DHT (100nM), or EST (100nM) for 16h or 24h. We employed a Seahorse analyzer to monitor glycolysis (as extracellular acidification rate, ECAR) and oxygen consumption rate (OCR). Changes in ECAR and OCR were related to the extracellular glucose levels, intracellular ATP, oxidative stress (O2), apoptosis (phosphatidilserine, PS) and cell diameter (n=4-6/group). Secreted levels of 15 chemokines/cytokines were quantified through a Multiplex Bead-Based Assay.

Results

Male PTECs showed significantly increased ECAR and OCR, ATP-linked respiration, maximal glycolitic and respiratory capacity, O2 and PS levels than female PTECs. In male PTECs, ECAR was increased after DHT stimulation, whereas OCR was increased by DHT and EST at baseline and in response to mitochondrial stress. In male PTECs, glucose concentration in the media was reduced by DHT treatment and glucose reduction was prevented by androgen receptor inhibitors. In turn, ATP, O2,PS levels, cell diameter and secretion of cytokines IL-6 and MCP1 were increased by DHT. DHT also augmented ATP levels in female PTECs. Interestingly, both DHT and EST increased ECAR and OCR in the PTECs from only one of the female donors.

Conclusion

DHT-induced proteome alterations are linked to a more glycolytic and oxidative phenotype in the human renal cell, and to higher glucose consumption, oxidative stress, apoptosis, IL-6/MCP1 secretion, and hypetrophy. Moreover, the metabolic function of PTECs and their susceptibility to sex hormones vary depending on the sex of the donor. Thus, not only hormonal but also (epi)genetic factors may contribute to a sex dimorphism in human renal metabolism.