1. Female Protection Against Diabetic Kidney Disease Is Regulated by Kidney-Specific AMPK Activity.
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Lee, Hak Joo, Min, Liang, Gao, Jingli, Matta, Shane, Drel, Viktor, Saliba, Afaf, Tamayo, Ian, Montellano, Richard, Hejazi, Leila, Maity, Soumya, Xu, Guogang, Grajeda, Brian I., Roy, Sourav, Hallows, Kenneth R., Choudhury, Goutam Ghosh, Kasinath, Balakuntalam S., and Sharma, Kumar
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DIABETIC nephropathies , *AMP-activated protein kinases , *KIDNEY tubules , *EXTRACELLULAR matrix proteins , *CHRONIC kidney failure - Abstract
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 was evaluated in diabetic kidney tubule–specific AMPKγ2KO (KTAMPKγ2ΚΟ) male and female mice. In wild-type (WT) males, diabetes increased albuminuria, urinary kidney injury molecule-1, hypertension, kidney p70S6K phosphorylation, and kidney matrix accumulation; these features were not exacerbated with KTAMPKγ2ΚΟ. Whereas WT females had protection against diabetes-induced kidney injury, KTAMPKγ2ΚΟ led to loss of female protection against kidney disease. The hormone 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 sequencing 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. Article Highlights: The basis for protection against kidney disease injury associated with obesity and diabetes in females is not known. In the present studies, genetic deletion of kidney tubule–specific gamma subunit of AMPK led to loss of female protection against diabetic kidney injury along with dysregulation of phenylalanine and tyrosine degradation. These new data indicate that AMPK in the kidney is critical for diabetic kidney disease. Importantly, differential regulation of kidney AMPK contributes to sex disparities. Our results provide a previously unrecognized mechanism for the development of precision treatments in sex dependence. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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