Cell Sex and Sex Hormones Modulate Kidney Glucose and Glutamine Metabolism in Health and Diabetes
Bibliographic record
Abstract
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. Conclusions: 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".