Program of Physiological and Pathological Processes, Centro de Biología Molecular "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain.
Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain.
J Clin Invest. 2021 Mar 1;131(5). doi: 10.1172/JCI140695.
Chronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present 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 whether gain of function in FAO (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1A (CPT1A) in TECs. Cpt1a-knockin (CPT1A-KI) mice subjected to 3 models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy [FAN], and adenine-induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted proinflammatory response, and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restored oxidative metabolism and mitochondrial number and enhanced bioenergetics, increasing palmitate oxidation and ATP levels, changes that were also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients showed decreased CPT1 levels and increased accumulation of short- and middle-chain acylcarnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD.
慢性肾脏病（CKD）仍然是一个主要的流行病学、临床和生物医学挑战。在 CKD 中，肾小管上皮细胞（TEC）呈现持续的炎症和纤维化反应。脂肪酸氧化（FAO）是 TEC 的主要能量来源，在肾脏纤维化中减少，并有助于其发病机制。为了确定 FAO 的功能获得（FAO-GOF）是否可以保护免受纤维化，我们在 TEC 中过表达脂肪酸穿梭酶肉毒碱棕榈酰转移酶 1A（CPT1A），生成了一种条件性转基因小鼠模型。CPT1A 敲入（CPT1A-KI）小鼠在 3 种肾纤维化模型（单侧输尿管梗阻、叶酸肾病[FAN]和腺嘌呤诱导的肾毒性）中表现出纤维化标志物表达减少、促炎反应减弱、上皮细胞损伤和巨噬细胞浸润减少。在 FAN 后诱导 Cpt1a 过表达时也观察到对纤维化的保护。FAO-GOF 恢复了氧化代谢和线粒体数量，并增强了生物能量，增加了棕榈酸氧化和 ATP 水平，这些变化也在暴露于促纤维化刺激的 TEC 中重现。在患者中的研究表明 CPT1 水平降低，短链和中链酰基辅酶 A 积累增加，反映了人类 CKD 中 FAO 的受损。我们提出，基于 FAO-GOF 的策略可能构成对抗 CKD 固有纤维化的有力替代方案。
