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Published on: September 20, 2021
Intercellular Communication Network of CellChat Uncovers Mechanisms of Kidney Fibrosis Based on Single-Cell RNA
Lei Lei1, Yun-Xiu Xiang1, Mao-Lin Luo2,3
1Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
Background:
Chronic kidney disease (CKD) is a global health concern, with renal fibrosis being a major pathological feature. Empagliflozin (Empa), a sodium-glucose co-transporter-2 inhibitor, has shown promise in protecting the kidney. This study aimed to investigate the effects of Empa on renal fibrosis in a nondiabetic CKD model and to elucidate the underlying mechanisms.
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 Empa-treated 5/6 Nx rats. Kidney function was assessed by measuring blood urea nitrogen, serum creatinine, and urinary albumin-to-creatinine ratio. Renal fibrosis was evaluated histologically. Single-cell RNA sequencing (scRNA-seq) was performed to analyze intercellular communication networks and identify alterations in ligand-receptor pairs and signaling pathways involved in fibrosis.
Results:
Empa treatment significantly improved kidney function and reduced renal interstitial fibrosis in 5/6 Nx rats. scRNA-seq revealed that Empa modulated the TGF-β signaling pathway, inhibited intercellular communication, and reduced the expression of fibrotic genes such as COLLAGEN, FN1, THBS, and LAMININ. Furthermore, Empa downregulated GRN gene expression, weakened signal transmission in the MIF pathway, consequently reduced the interaction between M2 macrophages and other cell types, such as endothelial cells, fibroblasts, and mesangial cells.
Conclusion:
This study elucidates the potential mechanisms by which Empa slows the progression of renal fibrosis in nondiabetic CKD. By reducing the number of M2 macrophages and inhibiting signal transduction in both pro-inflammatory and fibrotic pathways, Empa modulates the intercellular communication network in renal cells, offering a promising therapeutic strategy for CKD management.
Insights
Empagliflozin (Empa) reduces kidney fibrosis in chronic kidney disease (CKD) by modulating cell communication and inhibiting pro-fibrotic pathways. This sodium-glucose co-transporter-2 inhibitor offers a potential therapeutic strategy for CKD management.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Chronic kidney disease (CKD) affects millions globally, with renal fibrosis as a key pathological driver.
- Empagliflozin (Empa), a sodium-glucose co-transporter-2 inhibitor, demonstrates potential in kidney protection.
- Investigating Empa's effects on renal fibrosis in a nondiabetic CKD model is crucial for understanding its therapeutic mechanisms.
Purpose of the Study:
- To investigate the efficacy of Empagliflozin (Empa) in ameliorating renal fibrosis in a nondiabetic chronic kidney disease (CKD) model.
- To elucidate the underlying molecular and cellular mechanisms by which Empa exerts its renoprotective effects.
Main Methods:
- A 5/6 nephrectomy (5/6 Nx) rat model was used to induce CKD, with groups receiving placebo or Empa treatment.
- Kidney function was assessed via blood urea nitrogen, serum creatinine, and albumin-to-creatinine ratio.
- Single-cell RNA sequencing (scRNA-seq) analyzed intercellular communication, ligand-receptor interactions, and signaling pathways involved in fibrosis.
Main Results:
- Empa treatment significantly improved kidney function and attenuated renal interstitial fibrosis in 5/6 Nx rats.
- scRNA-seq identified Empa's modulation of the TGF-β and MIF signaling pathways, reducing fibrotic gene expression (e.g., COLLAGEN, FN1).
- Empa downregulated GRN expression, decreased M2 macrophage interactions with other renal cells, and inhibited pro-inflammatory and fibrotic signaling.
Conclusions:
- Empagliflozin (Empa) effectively slows renal fibrosis progression in nondiabetic CKD by targeting intercellular communication networks.
- Empa reduces M2 macrophage populations and inhibits pro-inflammatory and fibrotic signaling pathways, offering a novel therapeutic avenue.
- This study provides mechanistic insights into Empa's renoprotective effects, supporting its potential role in CKD management.
