Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON M5G 2C4, Canada.
Sci Transl Med. 2024 Mar 6;16(737):eabm2090. doi: 10.1126/scitranslmed.abm2090.
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.
糖尿病肾病（DKD）是慢性肾脏病（CKD）的主要病因，且男性患者的病情进展速度快于女性。我们鉴定了糖尿病男性和女性个体的肾脏代谢以及血液代谢组之间存在的性别差异。与健康女性的原代人近端肾小管上皮细胞（PTEC）相比，暴露于高葡萄糖环境下的健康男性的 PTEC 表现出更高的线粒体呼吸、氧化应激、细胞凋亡以及更大的损伤。人源男性 PTEC 表现出更高的葡萄糖和谷氨酰胺向 TCA 循环的通量，而女性 PTEC 则表现出更高的丙酮酸含量。二氢睾酮增强了人源男性 PTEC 表型，该作用由转录因子 HNF4A 和组蛋白去甲基化酶 KDM6A 介导。在性染色体与性腺性别匹配或不匹配的小鼠中，雄性性腺性别促成了雄性和雌性之间的肾脏代谢差异。在一组患有或未患有糖尿病的青少年的血液代谢组学分析中，男性的 TCA 循环代谢物增加。在第二组患有糖尿病的成年人中，无 DKD 的女性的血清丙酮酸浓度高于有或无 DKD 的男性。血清丙酮酸浓度与估计的肾小球滤过率（一种衡量肾脏功能的指标）呈正相关，与该队列的全因死亡率呈负相关。在第三组患有 CKD 的成年人中，男性性别和糖尿病与血浆 TCA 循环代谢物增加相关，这与全因死亡率相关。这些发现表明，男性和女性肾脏代谢的差异可能导致 DKD 中存在性别依赖性结果。
