Mouse Kidney MS - Standas diet WT/ High fat diet WT/ Standard diet ANT2 KO/ High fat diet ANT2 KO

Impairments in ATP production and transport in renal proximal tubule cells (RPTCs) result in obesity-induced chronic kidney disease (CKD), manifested by kidney dysfunction, inflammation, adiposity, and fibrosis. Here we assessed the role of adenine nucleotide transporter 2 (ANT2), the main regulator of cellular ATP content in RPTCs, in the development of obesity-induced CKD and its metabolic abnormalities. Obese RPTC-ANT2-/- mice exhibited normal renal morphology, function, and lack of kidney adiposity and fibrosis as well as an improvement in whole-body energy metabolism, manifested by normal glucose and lipid homeostasis and reduced hepatic steatosis. ANT2-depleted RPTCs rewired their primary metabolic program from oxidizing fatty acids as a primary energy source toward aerobic glycolysis, mediated via the testis-selective ANT4. We propose that RPTC-ANT2 plays an important role in the development of obesity-induced CKD, and that its nullification triggers mitochondrial protection, RPTC cellular survival, kidney preservation, and improvements in systemic metabolism.