ABSTRACT
Male sex is a risk factor for progression of diabetic kidney disease, but the reasons for this predilection are unclear. Here, we demonstrate that cell sex and sex hormones alter the metabolic phenotype of human proximal tubular epithelial cells (PTECs). Male PTECs displayed increased glycolysis, mitochondrial respiration, oxidative stress, apoptosis, and high glucose-induced injury, compared to female PTECs. This phenotype was enhanced by dihydrotestosterone (DHT) and linked to increased mitochondrial utilization of glucose and glutamine. Studies in vivo pointed towards increased glutamine anaplerosis in diabetic male kidneys. 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. Conversely, female PTECs displayed increased levels of pyruvate, glutamyl-cysteine, cysteinylglycine, and a higher GSH/GSSG ratio than male PTECs, indicative of enhanced redox homeostasis. 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. This work uncovers the role of sex in glucose/glutamine metabolism, that may explain the roots of sex dimorphism in the healthy and diabetic kidney.
Competing Interest Statement
The authors of this manuscript have conflicts of interest to disclose. Dr. Igor Jurisica reports receiving personal fees from Canadian Rheumatology Association, grants and nonfinancial support from IBM, and personal fees from Novartis, outside the submitted work. Dr. Maria Jose Soler reports honorarium for conferences, consulting fees and/or advisory boards from Astra Zeneca, NovoNordsik, Esteve, Vifor, Bayer, Mundipharma, Ingelheim Lilly, Jansen, ICU Medical, and Boehringer. All other authors have declared that no conflict of interest exists.
