Rationale: The present understanding of the cellular characteristics and communications in crystal nephropathy is limited. Here, molecular and cellular studies combined with single-cell RNA sequencing (scRNA-seq) were performed to investigate the changes in cell components and their interactions in glyoxylate-induced crystallized kidneys to provide promising treatments for crystal nephropathy./nMethods: The transcriptomes of single cells from mouse kidneys treated with glyoxylate for 0, 1, 4, or 7 days were analyzed via 10× Genomics, and the single cells were clustered and characterized by the Seurat pipeline. The potential cellular interactions between specific cell types were explored by CellChat. Molecular and cellular findings related to macrophage-to-epithelium crosstalk were validated in sodium oxalate (NaOx)-induced renal tubular epithelial cell injury in vitro and in glyoxylate-induced crystal nephropathy in vivo./nResults: Our established scRNA atlas of glyoxylate-induced crystalline nephropathy contained 15 cell populations with more than 40000 single cells, including relatively stable tubular cells of different segments, proliferating and injured proximal tubular cells, T cells, B cells, and myeloid and mesenchymal cells. In this study, we found that Mrc1⁺ macrophages, as a subtype of myeloid cells, increased in both the number and percentage within the myeloid population as crystal-induced injury progresses, and distinctly express IGF1, which induces the activation of a signal pathway to dominate a significant information flow towards injured and proliferating tubule cells. IGF1 promoted the repair of damaged tubular epithelial cells induced by NaOx in vitro, as well as the repair of damaged tubular epithelial cells and the recovery of disease outcomes in glyoxylate-induced nephrolithic mice in vivo./nConclusion: After constructing a cellular atlas of glyoxylate-induced crystal nephropathy, we found that IGF1 derived from Mrc1⁺ macrophages attenuated crystal nephropathy through promoting renal tubule cell proliferation via the AKT/Rb signaling pathway. These findings could lead to the identification of potential therapeutic targets for the treatment of crystal nephropathy.

中文翻译：

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Mrc1+ 巨噬细胞衍生的 IGF1 通过 AKT/Rb 信号通路促进肾小管细胞增殖，从而减轻晶体肾病

理由：目前对晶体肾病细胞特征和通讯的了解有限。在这里，进行了分子和细胞研究与单细胞 RNA 测序 (scRNA-seq) 相结合，以研究乙醛酸诱导的结晶肾中细胞成分的变化及其相互作用，从而为晶体肾病提供有希望的治疗方法。/n 方法：转录组通过 10× Genomics 分析来自用乙醛酸盐处理 0、1、4 或 7 天的小鼠肾脏的单细胞，并通过 Seurat 管道对单细胞进行聚类和表征。CellChat 探索了特定细胞类型之间潜在的细胞相互作用。与巨噬细胞与上皮细胞串扰相关的分子和细胞研究结果在体外草酸钠 (NaOx) 诱导的肾小管上皮细胞损伤和体内乙醛酸诱导的晶体肾病中得到了验证。/n 结果：我们建立的乙醛酸 scRNA 图谱诱导性结晶性肾病包含15个细胞群，超过40000个单细胞，包括相对稳定的不同节段的肾小管细胞、增殖和损伤的近端肾小管细胞、T细胞、B细胞以及骨髓和间质细胞。在这项研究中，我们发现 Mrc1 ⁺巨噬细胞作为骨髓细胞的一种亚型，随着晶体诱导损伤的进展，骨髓细胞群中的数量和百分比均增加，并明显表达 IGF1，从而诱导信号通路的激活主导着流向受损和增殖的小管细胞的重要信息流。IGF1在体外促进NaOx诱导的受损肾小管上皮细胞的修复，在体内促进乙醛酸诱导的肾石症小鼠受损肾小管上皮细胞的修复和疾病结局的恢复。/n结论：构建了细胞图谱后在乙醛酸诱导的晶体肾病中，我们发现源自 Mrc1 ⁺巨噬细胞的 IGF1 通过 AKT/Rb 信号通路促进肾小管细胞增殖来减轻晶体肾病。这些发现可能有助于确定治疗晶体肾病的潜在治疗靶点。