Divergent effects of AKI to CKD models on inflammation and fibrosis
Divergent effects of AKI to CKD models on inflammation and fibrosis
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DOI：
10.1152/ajprenal.00179.2018
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发表时间：
2018-10-01
影响因子：
4.2
通讯作者：
Agarwal, A.
中科院分区：
文献类型：
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作者：
Black, L. M.;Lever, J. M.;Agarwal, A.
慢性肾脏疾病(CKD)是一种发病率和死亡率都很高的疾病，在美国有15%的成年人受到影响。CKD的一个原因是急性肾损伤(AKI)，它通常继发于脓毒症、缺血事件和药物引起的肾毒性。无对侧肾切除(CLN)的单侧缺血再灌注损伤(UIRI)和反复小剂量顺铂(RLDC)AKI-CKD模型显示了这种转变的反应特征；然而，以前的研究并未有效地比较其发病机制。我们证明这两种模型都会引发肾功能障碍、炎性细胞因子反应和纤维化。然而，这两种模型在尿液排泄功能、炎性细胞浸润和纤维化反应程度方面表现出差异。无CLN的UIRI表现为对侧肾血流灌注和功能恶化，对侧肾脏生理代偿。此外，在没有CLN的情况下，UIRI引起了强烈的炎症反应，其特征是多形核细胞和自然杀伤细胞浸润时间延长，肾脏滞留巨噬细胞早期扩张，随后T细胞浸润。对称性功能减退发生在RLDC肾脏，并逐渐恶化，直到研究的第17天。令人惊讶的是，与对照组相比，RLDC小鼠表现出炎症细胞数量的减少。然而，RLDC肾脏表达增加的肾脏损伤分子-1(Kim-1)、高迁移率族蛋白-1(HMGB1)和集落刺激因子-1(CSF-1)，这可能是招募炎症细胞的损伤反应。这些数据强调了AKI到CKD模型的不同病因如何影响肾脏微环境和预后。这项研究为人类研究中AKI的病因学亚型提供了支持，有助于阐明AKI向CKD转变的损伤特异性病理生理机制。
Chronic kidney disease (CKD) is a condition with significant morbidity and mortality that affects 15% of adults in the United States. One cause of CKD is acute kidney injury (AKI), which commonly occurs secondary to sepsis, ischemic events, and drug-induced nephrotoxicity. Unilateral ischemia-reperfusion injury (UIRI) without contralateral nephrectomy (CLN) and repeated low-dose cisplatin (RLDC) models of AKI to CKD demonstrate responses characteristic of the transition; however, previous studies have not effectively compared the pathogenesis. We demonstrate both models instigate renal dysfunction, inflammatory cytokine responses, and fibrosis. However, the models exhibit differences in urinary excretory function, inflammatory cell infiltration, and degree of fibrotic response. UIRI without CLN demonstrated worsening perfusion and function, measured with Tc-99m-mercaptoacetyltriglycine-3 imaging, and physiologic compensation in the contralateral kidney. Furthermore, UIRI without CLN elicited a robust inflammatory response that was characterized by a prolonged polymorphonuclear cell and natural killer cell infiltrate and an early expansion of kidney resident macrophages, followed by T-cell infiltration. Symmetrical diminished function occurred in RLDC kidneys and progressively worsened until day 17 of the study. Surprisingly, RLDC mice demonstrated a decrease in inflammatory cell numbers relative to controls. However, RLDC kidneys expressed increased levels of kidney injury molecule-1 (KIM-1), high mobility group box-1 (HMGB1), and colony stimulating factor-1 (CSF-1), which likely recruits inflammatory cells in response to injury. These data emphasize how the divergent etiologies of AKI to CKD models affect the kidney microenvironment and outcomes. This study provides support for subtyping AKI by etiology in human studies, aiding in the elucidation of injury-specific pathophysiologic mechanisms of the AKI to CKD transition.