Intercellular Communication Network of CellChat Uncovers Mechanisms of Kidney Fibrosis Based on Single-Cell RNA Sequencing

Abstract

Abstract Background Anti-renal fibrosis and the postponement of renal function are global challenges in treating chronic kidney disease (CKD). However, sodium-glucose cotransporter 2 (SGLT2) inhibitors have opened new avenues for treating diabetic nephropathy. Researchers are currently investigating the potential advantages of SGLT2 inhibitors for non-diabetic CKD. Methods We established a CKD model using 5/6 nephrectomy (5/6 Nx) rats and divided them into three groups: placebo-treated sham surgery rats, placebo-treated 5/6 Nx rats, and Empagliflozin (Empa)-treated 5/6 Nx rats. We performed single-cell RNA sequencing on the kidneys of 5/6 Nx rats and used CellChat for quantitative inference and analysis of intercellular communication networks. Results Intercellular analysis revealed that the probability and intensity of universal communications were higher in the kidneys of 5/6 Nx rats treated with placebo than in rats treated with sham surgery and placebo. 5/6 Nx up-regulated MIF and GRN expression in tubular epithelial cells, which were activated by paracrine signaling from M2 macrophages. TGF-β also plays an important role in regulating endothelial, mesangial, and fibroblast cells by inducing the up-regulation of fibrogenic genes. This process promotes collagen synthesis and extracellular matrix deposition by activating the COLLAGEN, FN1, LAMNIN, and THBS pathways. In addition, Empa treatment improves renal morphology in 5/6 Nx rats by inhibiting MIF and GRN expression in tubular epithelial cells and down-regulating the COLLAGEN, FN1, THBS, and LAMNIN pathways associated with kidney fibrosis. Conclusion We identified critical ligand-receptor pairs and signaling pathways involved in CKD fibrosis by leveraging the intercellular communication network of CellChat. Moreover, our findings indicate that Empa can reduce renal fibrosis in CKD by modulating the intercellular communication network and signaling pathways.