American Diabetes Association
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AMPK_G2_KO_supplemental_data_diabetes.pdf (2.33 MB)

Female protection against diabetic kidney disease is regulated by kidney-specific AMPK activity

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posted on 2024-04-24, 17:19 authored by Hak Joo Lee, Liang Min, Jingli Gao, Shane Matta, Viktor Drel, Afaf Saliba, Ian Tamayo, Richard Montellano, Leila Hejazi, Soumya Maity, Guogang Xu, Brian I. Grajeda, Sourav Roy, Kenneth R. Hallows, Goutam Ghosh Choudhury, Balakuntalam S. Kasinath, Kumar Sharma

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 AMPKg2KO (KTAMPKg2ΚΟ) 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 KTAMPKg2ΚΟ. Whereas WT females had protection against diabetes induced kidney injury, KTAMPKg2ΚΟ led to loss of female protection against kidney disease. 17b-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.

Funding

This work is supported by the Veterans Affairs Biomedical Laboratory Research and Development Service (VA) I101BX001340 to HJL, BSK and KS. HJL and KS is supported by VA Merit Review grant I101BX003234. GGC is supported by VA Merit Review grant 2I01 BX000926. GGC is recipient of Research Career Scientist Award IK6 BX005795 from the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. SR is supported by UTEP CoS Start-Up grant 19508430. AS is supported by NIH/NCATS, TL1 TR002647.

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