y acid oxidation to aerobic glycolysis, resulting in mitochondrial protection, cellular survival, and preservation of renal function. These findings provide new insights into the underlying mechanisms of obesity-induced CKD and have the potential to be translated toward the development of targeted therapeutic strategies for this debilitating condition. Background The impairment in ATP production and transport in RPTCs has been linked to the pathogenesis of obesity-induced CKD. This condition is characterized by kidney dysfunction, inflammation, lipotoxicity, and fibrosis. In this study, we investigated the role of 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. In addition, we used 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....

中文翻译：

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肾线粒体 ATP 转运蛋白消融可改善肥胖引起的 CKD

y 酸氧化为有氧糖酵解，从而保护线粒体、细胞存活和肾功能的保存。这些发现为肥胖引起的 CKD 的潜在机制提供了新的见解，并有可能转化为针对这种衰弱疾病的靶向治疗策略的开发。背景 RPTC 中 ATP 生成和运输的受损与肥胖引起的 CKD 的发病机制有关。这种病症的特征是肾功能障碍、炎症、脂毒性和纤维化。在这项研究中，我们研究了 ANT2 在肥胖引起的 CKD 发展中的作用，ANT2 作为 RPTC 中细胞 ATP 含量的主要调节因子。方法 我们培育了 RPTC 特异性 ANT2 敲除 (RPTC-ANT2−/−) 小鼠，然后对其进行为期 24 周的高脂肪饮食喂养方案。我们对这些小鼠的肾脏形态、功能和代谢变化进行了全面评估。此外，我们还利用大规模转录组学、蛋白质组学和代谢组学分析来深入了解 ANT2 在调节线粒体功能、RPTC 生理学和整体肾脏健康中的作用。结果我们的研究结果表明，肥胖的 RPTC-ANT2−/− 小鼠表现出保留的肾脏形态和功能，并且明显缺乏肾脏脂肪毒性和纤维化。RPTC 中 Ant2 的消耗导致其主要代谢程序发生根本性的重新布线。具体来说，这些细胞从氧化脂肪酸作为主要能量来源转变为有利于有氧糖酵解，这是由睾丸选择性 Ant4 介导的现象。结论 我们提出 RPTC-Ant2 在肥胖诱导的 CKD 发展中发挥重要作用。RPTC-Ant2 的失效会触发一系列细胞机制，包括线粒体保护、增强 RPTC 存活率，并最终保留肾功能。这些发现为促进 CKD 发展的复杂代谢途径提供了新的线索，并提出了这种情况的潜在治疗靶点......