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.

中文翻译：

---

肾脏代谢的性别差异可能反映了人类糖尿病肾病的性别依赖性结果

糖尿病肾病（DKD）是慢性肾病（CKD）的主要原因，男性的进展速度比女性快。我们确定了男性和女性糖尿病患者肾脏代谢和血液代谢组中基于性别的差异。与来自健康女性的 PTEC 相比，来自健康男性的原代人近端肾小管上皮细胞 (PTEC) 在暴露于高葡萄糖时表现出增加的线粒体呼吸、氧化应激、细胞凋亡和更大的损伤。男性人类 PTEC 显示出增加的 TCA 循环葡萄糖和谷氨酰胺通量，而女性人类 PTEC 显示出增加的丙酮酸含量。男性 PTEC 表型通过二氢睾酮增强，并由转录因子 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，雄性性腺性别导致了雄性和雌性之间肾脏代谢的差异。对患有或不患有糖尿病的青少年队列进行的血液代谢组学分析显示，男性的 TCA 循环代谢物增加。在第二组成年糖尿病患者中，未患 DKD 的女性血清丙酮酸浓度高于患有或未患有 DKD 的男性。在该队列中，血清丙酮酸浓度与估计的肾小球滤过率（肾功能的衡量标准）呈正相关，与全因死亡率呈负相关。在第三组患有 CKD 的成年人中，男性和糖尿病与血浆 TCA 循环代谢物增加有关，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 的性别依赖性结果。