Mrc1+ macrophage-derived IGF1 mitigates crystal nephropathy by promoting renal tubule cell proliferation via the AKT/Rb signaling pathway.

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. Methods: 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. Results: 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. Conclusion: 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.

Yi-Shen-Hua-Shi Granule Alleviates Adriamycin-Induced Glomerular Fibrosis by Suppressing the BMP2/Smad Signaling Pathway.

Focal segmental glomerulosclerosis (FSGS) is a common clinical condition with manifestations of nephrotic syndrome and fibrosis of the glomeruli and interstitium. Yi-Shen-Hua-Shi (YSHS) granule has been shown to have a good effect in alleviating nephrotic syndrome (NS) in clinical and in animal models of FSGS, but whether it can alleviate renal fibrosis in FSGS and its mechanism and targets are not clear. In this study, we explored the anti-fibrotic effect and the targets of the YSHS granule in an adriamycin (ADR)-induced FSGS model and found that the YSHS granule significantly improved the renal function of ADR-induced FSGS model mice and also significantly reduced the deposition of collagen fibers and the expression of mesenchymal cell markers FN, vimentin, and α-SMA in the glomeruli of ADR-induced FSGS mice, suggesting that the YSHS granule inhibited the fibrosis of sclerotic glomeruli. Subsequently, a network pharmacology-based approach was used to identify the potential targets of the YSHS granule for the alleviation of glomerulosclerosis in FSGS, and the results showed that the YSHS granule down-regulated the expressions of BMP2, GSTA1, GATS3, BST1, and S100A9 and up-regulated the expressions of TTR and GATM in ADR-induced FSGS model mice. We also proved that the YSHS granule inhibited the fibrosis in the glomeruli of ADR-induced FSGS model mice through the suppression of the BMP2/Smad signaling pathway.