Anna Permyakova, Sharleen Hamad, Liad Hinden, Saja Baraghithy, Aviram Kogot-Levin, Omri Yosef, Ori Shalev, Manish Kumar Tripathi, Haitham Amal, Abhishek Basu, Muhammad Arif, Resat Cinar, George Kunos, Michael Berger, Gil Leibowitz, Joseph Tam

Renal Mitochondrial ATP Transporter Ablation Ameliorates Obesity-Induced Chronic Kidney Disease

  • Nephrology
  • General Medicine
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Background: The impairment in ATP production and transport in renal proximal tubule cells (RPTCs) has been linked to the pathogenesis of obesity-induced chronic kidney disease (CKD). This condition is characterized by kidney dysfunction, inflammation, lipotoxicity, and fibrosis. Here we investigated the role of adenine nucleotide transporter 2 (ANT2), which serves as the primary regulator of cellular ATP content in RPTCs, in the development of obesity-induced CKD. Methods: We generated RPTC-specific Ant2 knockout (RPTC-Ant2 -/-) mice, which were then subjected to a 24-week high-fat diet feeding regimen. We conducted comprehensive assessment of renal morphology, function, and metabolic alterations of these mice. Additionally, we employed large-scale transcriptomics, proteomics, and metabolomics analyses to gain insights into the role of ANT2 in regulating mitochondrial function, RPTC physiology, and overall renal health. Results: Our findings revealed that obese RPTC-Ant2 -/- mice displayed preserved renal morphology and function, along with a notable absence of kidney lipotoxicity and fibrosis. The depletion of Ant2 in RPTCs led to a fundamental rewiring of their primary metabolic program. Specifically, these cells shifted from oxidizing fatty acids as their primary energy source to favoring aerobic glycolysis, a phenomenon mediated by the testis-selective Ant4. Conclusions: We propose a significant role for RPTC-Ant2 in the development of obesity-induced CKD. The nullification of RPTC-Ant2 triggers a cascade of cellular mechanisms, including mitochondrial protection, enhanced RPTC survival, and ultimately the preservation of kidney function. These findings shed new light on the complex metabolic pathways contributing to CKD development and suggest potential therapeutic targets for this condition.

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