Department of Critical Care Medicine, Program for Critical Care Nephrology, The CRISMA Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Nephron. 2023;147(1):31-34. doi: 10.1159/000527392. Epub 2022 Nov 4.
The recognition that sepsis induces acute kidney injury (AKI) in the absence of overt necrosis or apoptosis and even in the presence of increased renal blood flow has led to the consideration that kidney tubular epithelial cells (TECs) may deploy defense mechanisms to survive the insult.
This concept dovetails well with the notion that the defense against infection not only depends on the capacity of the immune system to limit the microbial burden or resistance capacity but also on the capacity of the host to limit tissue injury, collectively known as tolerance. To sustain the high energy requirement that ion transport mandates, kidney TECs use fatty acid oxidation (FAO) as one of the preferred sources of energy. Inflammatory processes like endotoxemia and sepsis decrease mitochondrial FAO and hinder mitochondrial respiration. Impaired FAO is associated with TEC de-differentiation, loss of kidney function, and TEC injury through lipotoxicity and oxidative stress in the acute setting, and with maladaptive repair and fibrosis after AKI in the latter stages. AMP-activated protein kinase (AMPK) is a master regulator of energy and promoter of FAO that can be activated pharmacologically to protect against AKI and death during experimental sepsis, operating through a tolerance mechanism.
Organ dysfunction during sepsis is the expression of tissue injury and adaptive defense mechanisms operating through resistance or tolerance that prioritize cell survival over organ function. Metabolic reprogramming away from FAO/oxidative phosphorylation seems to be a common pathological denominator throughout the AKI continuum that may be targeted through the activation of AMPK.
人们认识到，即使在肾血流量增加的情况下，脓毒症也会导致急性肾损伤（AKI），而没有明显的坏死或凋亡，这使得人们认为肾小管上皮细胞（TEC）可能会启动防御机制来抵抗损伤。
这一概念与以下观点是一致的，即抗感染的防御不仅取决于免疫系统限制微生物负担或抵抗能力的能力，还取决于宿主限制组织损伤的能力，统称为耐受。为了维持离子转运所需的高能量需求，肾脏 TEC 使用脂肪酸氧化（FAO）作为首选能量来源之一。像内毒素血症和脓毒症这样的炎症过程会降低线粒体 FAO 并阻碍线粒体呼吸。在急性情况下，FAO 受损与 TEC 去分化、肾功能丧失以及通过脂毒性和氧化应激导致的 TEC 损伤有关，在 AKI 的后期阶段则与适应性修复和纤维化有关。AMP 激活的蛋白激酶（AMPK）是能量的主要调节剂和 FAO 的促进剂，可以通过药理学激活来预防实验性脓毒症中的 AKI 和死亡，通过耐受机制发挥作用。
脓毒症期间的器官功能障碍是组织损伤的表现，适应性防御机制通过抵抗或耐受起作用，这些机制优先考虑细胞存活而不是器官功能。从 FAO/氧化磷酸化转向代谢重编程似乎是 AKI 连续体中的一个常见病理共同特征，可以通过激活 AMPK 来靶向治疗。
