Laboratory of Basic Science in Renal Diseases (LIM-12), Division of Nephrology, School of Medicine, University of São Paulo, São Paulo, Brazil.
Department of Pathology, Amsterdam Cardiovascular Science and Amsterdam Infection and Immunity, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
J Pathol. 2024 Aug;263(4-5):496-507. doi: 10.1002/path.6302. Epub 2024 Jun 27.
Chronic kidney disease (CKD) has emerged as a significant global public health concern. Recent epidemiological studies have highlighted the link between exposure to fine particulate matter (PM) and a decline in renal function. PM exerts harmful effects on various organs through oxidative stress and inflammation. Acute kidney injury (AKI) resulting from ischaemia-reperfusion injury (IRI) involves biological processes similar to those involved in PM toxicity and is a known risk factor for CKD. The objective of this study was to investigate the impact of PM exposure on IRI-induced AKI. Through a unique environmentally controlled setup, mice were exposed to urban PM or filtered air for 12 weeks before IRI followed by euthanasia 48 h after surgery. Animals exposed to PM and IRI exhibited reduced glomerular filtration, impaired urine concentration ability, and significant tubular damage. Further, PM aggravated local innate immune responses and mitochondrial dysfunction, as well as enhancing cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation. This increased renal senescence and suppressed the anti-ageing protein klotho, leading to early fibrotic changes. In vitro studies using proximal tubular epithelial cells exposed to PM and hypoxia/reoxygenation revealed heightened activation of the STING pathway triggered by cytoplasmic mitochondrial DNA, resulting in increased tubular damage and a pro-inflammatory phenotype. In summary, our findings imply a role for PM in sensitising proximal tubular epithelial cells to IRI-induced damage, suggesting a plausible association between PM exposure and heightened susceptibility to CKD in individuals experiencing AKI. Strategies aimed at reducing PM concentrations and implementing preventive measures may improve outcomes for AKI patients and mitigate the progression from AKI to CKD. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
慢性肾脏病（CKD）已成为一个重大的全球公共卫生问题。最近的流行病学研究强调了细颗粒物（PM）暴露与肾功能下降之间的联系。PM 通过氧化应激和炎症对各种器官产生有害影响。缺血再灌注损伤（IRI）引起的急性肾损伤（AKI）涉及与 PM 毒性相关的类似生物学过程，并且是 CKD 的已知危险因素。本研究旨在探讨 PM 暴露对 IRI 诱导的 AKI 的影响。通过独特的环境控制设置，将小鼠暴露于城市 PM 或过滤空气中 12 周，然后进行 IRI，手术后 48 小时安乐死。暴露于 PM 和 IRI 的动物表现出肾小球滤过率降低、尿液浓缩能力受损和明显的肾小管损伤。此外，PM 加重了局部固有免疫反应和线粒体功能障碍，并增强了环鸟苷酸-腺苷酸合酶-干扰素基因刺激物（cGAS-STING）途径的激活。这增加了肾脏衰老并抑制了抗衰老蛋白 klotho，导致早期纤维化变化。体外研究使用暴露于 PM 和缺氧/复氧的近端肾小管上皮细胞表明，细胞质线粒体 DNA 触发的 STING 途径的高度激活导致肾小管损伤增加和促炎表型。总之，我们的研究结果表明 PM 在使近端肾小管上皮细胞易受 IRI 诱导的损伤方面发挥作用，提示 PM 暴露与经历 AKI 的个体对 CKD 的易感性增加之间存在可能的关联。旨在降低 PM 浓度和实施预防措施的策略可能会改善 AKI 患者的结局并减轻从 AKI 到 CKD 的进展。
