Reduced kidney AMPK activity is associated with nutrient stress-induced chronic kidney disease (CKD) in male mice. In contrast, female mice resist nutrient stress-induced CKD. The role of kidney AMPK in sex-related organ protection against nutrient stress and metabolite changes were evaluated in diabetic kidney tubule-specific AMPKγ2KO (KTAMPKγ2KO) male and female mice. In WT males, diabetes increased albuminuria, urinary kidney injury molecule-1, hypertension, kidney p70S6K phosphorylation, and kidney matrix accumulation; these features were not exacerbated with KTAMPKγ2KO. Whereas WT females had protection against diabetes induced kidney injury, KTAMPKγ2KO led to loss of female protection against kidney disease. 17β-estradiol ameliorated high glucose-induced AMPK inactivation, p70S6K phosphorylation and matrix protein accumulation in kidney tubule cells. The mechanism for female protection against diabetes-induced kidney injury is likely via an estrogen-AMPK pathway, as inhibition of AMPK led to loss of estrogen protection to glucose-induced mTORC1 activation and matrix production. RNA-seq and metabolomic analysis identified a decrease in the degradation pathway of phenylalanine and tyrosine resulting in increased urinary phenylalanine and tyrosine levels in females. The metabolite levels correlated with loss of female protection. The findings provide new insights to explain evolutionary advantages to females during states of nutrient challenges.

中文翻译：

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女性对糖尿病肾病的保护作用受到肾脏特异性 AMPK 活性的调节

雄性小鼠肾脏 AMPK 活性降低与营养应激诱发的慢性肾病 (CKD) 有关。相比之下，雌性小鼠可以抵抗营养应激引起的慢性肾病。在糖尿病肾小管特异性 AMPKγ2KO (KTAMPKγ2KO) 雄性和雌性小鼠中评估了肾脏 AMPK 在性相关器官保护中免受营养应激和代谢变化的作用。在 WT 男性中，糖尿病增加蛋白尿、尿肾损伤分子 1、高血压、肾脏 p70S6K 磷酸化和肾基质积累； KTAMPKγ2KO 不会加剧这些特征。 WT 女性具有针对糖尿病引起的肾损伤的保护作用，而 KTAMPKγ2KO 则导致女性失去针对肾病的保护作用。 17β-雌二醇改善高葡萄糖诱导的 AMPK 失活、p70S6K 磷酸化和肾小管细胞中基质蛋白的积累。女性预防糖尿病引起的肾损伤的机制可能是通过雌激素-AMPK 途径，因为抑制 AMPK 会导致雌激素失去对葡萄糖诱导的 mTORC1 激活和基质产生的保护。 RNA-seq 和代谢组学分析发现苯丙氨酸和酪氨酸降解途径减少，导致女性尿苯丙氨酸和酪氨酸水平增加。代谢物水平与女性保护的丧失相关。这些发现提供了新的见解来解释雌性在营养挑战状态下的进化优势。