Sex differences in kidney metabolism may reflect sex-dependent outcomes in human diabetic kidney disease.

Diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD) and progresses faster in males than in females. We identify sex-based differences in kidney metabolism and in the blood metabolome of male and female individuals with diabetes. Primary human proximal tubular epithelial cells (PTECs) from healthy males displayed increased mitochondrial respiration, oxidative stress, apoptosis, and greater injury when exposed to high glucose compared with PTECs from healthy females. Male human PTECs showed increased glucose and glutamine fluxes to the TCA cycle, whereas female human PTECs showed increased pyruvate content. The male human PTEC phenotype was enhanced by dihydrotestosterone and mediated by the transcription factor HNF4A and histone demethylase KDM6A. In mice where sex chromosomes either matched or did not match gonadal sex, male gonadal sex contributed to the kidney metabolism differences between males and females. A blood metabolomics analysis in a cohort of adolescents with or without diabetes showed increased TCA cycle metabolites in males. In a second cohort of adults with diabetes, females without DKD had higher serum pyruvate concentrations than did males with or without DKD. Serum pyruvate concentrations positively correlated with the estimated glomerular filtration rate, a measure of kidney function, and negatively correlated with all-cause mortality in this cohort. In a third cohort of adults with CKD, male sex and diabetes were associated with increased plasma TCA cycle metabolites, which correlated with all-cause mortality. These findings suggest that differences in male and female kidney metabolism may contribute to sex-dependent outcomes in DKD.

Three-Dimensional Analysis of Sex- and Gonadal Status- Dependent Microglial Activation in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by neurodegeneration and neuroinflammation. PD prevalence and incidence are higher in men than in women and modulation of gonadal hormones could have an impact on the disease course. This was investigated in male and female gonadectomized (GDX) and SHAM operated (SHAM) mice. Dutasteride (DUT), a 5α-reductase inhibitor, was administered to these mice for 10 days to modulate their gonadal sex hormones. On the fifth day of DUT treatment, mice received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model PD. We have previously shown in these mice the toxic effect of MPTP in SHAM and GDX males and in GDX females on dopamine markers and astrogliosis whereas SHAM females were protected by their female sex hormones. In SHAM males, DUT protected against MPTP toxicity. In the present study, microglial density and the number of doublets, representative of a microglial proliferation, were increased by the MPTP lesion only in male mice and prevented by DUT in SHAM males. A three-dimensional morphological microglial analysis showed that MPTP changed microglial morphology from quiescent to activated only in male mice and was not prevented by DUT. In conclusion, microgliosis can be modulated by sex hormone-dependent and independent factors in a mice model of PD.

Effect of sex and gonadectomy on brain MPTP toxicity and response to dutasteride treatment in mice.

The main neuropathological feature of Parkinson's disease (PD) is degeneration of dopamine (DA) neurons in the substantia nigra (SN); PD prevalence is higher in men, suggesting a role of sex hormones in neuroprotection. This study sought the effects of sex hormones in the brain in a mouse model of PD and modulation of steroid metabolism/synthesis with the 5α-reductase inhibitor dutasteride shown to protect 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) male mice. Male and female mice were gonadectomized (GDX) or SHAM operated. They were treated with vehicle or dutasteride (5 mg/kg) for 10 days and administered a low dose of MPTP (5.5 mg/kg) or saline on the 5th day to model early PD; brains were collected thereafter. Striatal measures of the active metabolite 1-methyl-4-phenylpyridinium (MPP+) contents showed no difference supporting an effect of the experimental conditions investigated. In SHAM MPTP male mice loss of striatal DA and metabolites, DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding in the striatum and SN was prevented by dutasteride treatment; these changes were inversely correlated with glial fibrillary acidic protein (GFAP, an astrogliosis marker) levels. In SHAM female mice MPTP treatment had little or no effect on striatal and SN DA markers and GFAP levels whereas GDX male and female mice showed a similar loss of striatal DA markers and increase of GFAP. No effect of dutasteride treatment was observed in GDX male and female mice. In conclusion, sex differences in mice MPTP toxicity and response to dutasteride were observed that were lost upon gonadectomy implicating neuroinflammation.