National Health Commission (NHC) Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, China.
Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu, China.
Nat Commun. 2024 May 23;15(1):4383. doi: 10.1038/s41467-024-47842-z.
Macrophages (Mφ) autophagy is a pivotal contributor to inflammation-related diseases. However, the mechanistic details of its direct role in acute kidney injury (AKI) were unclear. Here, we show that Mφ promote AKI progression via crosstalk with tubular epithelial cells (TECs), and autophagy of Mφ was activated and then inhibited in cisplatin-induced AKI mice. Mφ-specific depletion of ATG7 (Atg7) aggravated kidney injury in AKI mice, which was associated with tubulointerstitial inflammation. Moreover, Mφ-derived exosomes from Atg7 mice impaired TEC mitochondria in vitro, which may be attributable to miR-195a-5p enrichment in exosomes and its interaction with SIRT3 in TECs. Consistently, either miR-195a-5p inhibition or SIRT3 overexpression improved mitochondrial bioenergetics and renal function in vivo. Finally, adoptive transfer of Mφ from AKI mice to Mφ-depleted mice promotes the kidney injury response to cisplatin, which is alleviated when Mφ autophagy is activated with trehalose. We conclude that exosomal miR-195a-5p mediate the communication between autophagy-deficient Mφ and TECs, leading to impaired mitochondrial biogenetic in TECs and subsequent exacerbation of kidney injury in AKI mice via miR-195a-5p-SIRT3 axis.
巨噬细胞（Mφ）自噬是炎症相关疾病的关键贡献者。然而，其在急性肾损伤（AKI）中的直接作用的机制细节尚不清楚。在这里，我们表明 Mφ 通过与肾小管上皮细胞（TEC）的串扰促进 AKI 进展，并且顺铂诱导的 AKI 小鼠中的 Mφ 自噬被激活然后被抑制。Mφ 特异性敲除 ATG7（Atg7）加重 AKI 小鼠的肾脏损伤，这与肾小管间质炎症有关。此外，来自 Atg7 小鼠的 Mφ 衍生的外体在体外损害了 TEC 的线粒体，这可能归因于外体中 miR-195a-5p 的富集及其与 TEC 中的 SIRT3 的相互作用。一致地，miR-195a-5p 的抑制或 SIRT3 的过表达改善了体内的线粒体生物发生和肾功能。最后，将 AKI 小鼠的 Mφ 过继转移到 Mφ 耗竭的小鼠中会促进对顺铂的肾脏损伤反应，而用海藻糖激活 Mφ 自噬会减轻这种反应。我们得出结论，外泌体 miR-195a-5p 介导自噬缺陷的 Mφ 和 TEC 之间的通讯，导致 TEC 中线粒体生物发生受损，随后通过 miR-195a-5p-SIRT3 轴加重 AKI 小鼠的肾脏损伤。
