Chronic kidney disease (CKD) remains a major epidemiological, clinical and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) suffer a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine if FAO gain-of-function (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1 A (CPT1A) in TECs. Cpt1a knock-in (CPT1A KI) mice subjected to three different models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy-FAN and adenine induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted pro-inflammatory response and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restituted oxidative metabolism and mitochondrial number and enhanced bioenergetics increasing palmitate oxidation and ATP levels, changes also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients evidenced decreased CPT1 levels and increased accumulation of short and middle chain acyl-carnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD.

中文翻译：

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肾小管Cpt1a过表达通过恢复线粒体体内稳态来保护其免受肾脏纤维化的侵害

慢性肾脏病（CKD）仍然是主要的流行病学，临床和生物医学挑战。在CKD期间，肾小管上皮细胞（TECs）遭受持续的炎症和纤维化反应。脂肪酸氧化（FAO）是TECs的主要能量来源，在肾脏纤维化中减少，并有助于其发病。为了确定粮农组织的功能获得（FAO-GOF）是否可以防止纤维化，我们建立了条件转基因小鼠模型，其在TECs中过表达脂肪酸穿梭酶肉碱棕榈酰转移酶1A（CPT1A）。Cpt1a敲入（CPT1A KI）小鼠经历了三种不同模型的肾纤维化（单侧输尿管阻塞，叶酸肾病-FAN和腺嘌呤诱导的肾毒性），其纤维化标记物的表达降低，炎症反应减弱，上皮细胞损伤和巨噬细胞流入减少。在FAN后诱导Cpt1a过表达时，也观察到了针对纤维化的保护作用。FAO-GOF恢复了氧化代谢和线粒体数量，并增强了生物能，从而增加了棕榈酸酯的氧化和ATP含量，而且在暴露于原纤维化刺激的TECs中也概括了这种变化。对患者的研究表明，CPT1水平降低，短链和中链酰基肉碱的积累增加，反映出人类CKD中的FAO受损。我们建议，以粮农组织-全球政府框架为基础的战略可能构成抗击CKD固有纤维化的有力替代方案。FAO-GOF恢复了氧化代谢和线粒体数量，并增强了生物能，从而增加了棕榈酸酯的氧化和ATP含量，而且在暴露于纤维化刺激的TECs中也概括了这种变化。对患者的研究表明，CPT1水平降低，短链和中链酰基肉碱的积累增加，反映出人类CKD中的FAO受损。我们建议，以粮农组织-全球政府框架为基础的战略可能构成抗击CKD固有纤维化的有力替代方案。FAO-GOF恢复了氧化代谢和线粒体数量，并增强了生物能，从而增加了棕榈酸酯的氧化和ATP含量，而且在暴露于纤维化刺激的TECs中也概括了这种变化。对患者的研究表明，CPT1水平降低，短链和中链酰基肉碱的积累增加，反映出人类CKD中的FAO受损。我们建议，以粮农组织-全球政府框架为基础的战略可能构成抗击CKD固有纤维化的有力替代方案。