Abstract: FR-PO367
Single-Cell Genomics Applied to Unilateral Ureteral Obstruction Kidneys with Lymphatic Vessel Knockdown Identifies the Key Role of Adaptive Immunity in Renal Fibrosis
Session Information
- CKD: Mechanisms - II
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Wu, Jianliang, Tongji Hospital, Huazhong Univ of Science and Technology, Wuhan, Hubei, China
- Ma, Zhimei, Wuhan Biobank Co., Ltd., Wuhan, China
- Guo, Jing, Wuhan Biobank Co., Ltd., Wuhan, China
- Xu, Gang, Tongji Hospital, Huazhong Univ of Science and Technology, Wuhan, Hubei, China
- Zeng, Rui, Tongji Hospital, Huazhong Univ of Science and Technology, Wuhan, Hubei, China
Background
Lymphangiogenesis in chronic kidney disease has been reported in a large number of literatures. However, it is still unclear how the lymphatic vessels (LVs) act as a transport channel regulating the infiltration of immune cells in the kidney. The purpose of this study was to clarify the mechanisms by which LVs regulate the infiltration of immune cells and the following chronic kidney disease and fibrosis.
Methods
We constructed four lymphatic knockdown mouse models. The new-born proliferated LVs were knockdown by injection of Ganciclovir after unilateral ureteral obstruction (UUO) in Lyve-1-tk and Prox-1-tk mice, and resident LVs were knockdown by injection of DT in Lyve-1-DTR and Prox-1-DTR mice. Then, we performed RNA-Seq and single-cell transcriptomics on the kidneys of lymphatic knockdown group and control group.
Results
It showed that the UUO kidney had less LVs, less inflammatory cell infiltration and reduced fibrosis after new-born proliferated LVs or resident LVs knockdown. The ischemia reperfusion injury model yields the similar results. Both differentially expressed genes (DEGs), GO and KEGG pathway analysis identified that DEGs are mainly enriched in chemokine related genes. The heat map showed that chemokines and renal extracellular matrix deposition related genes were significantly down-regulated after lymphatic knockdown. The single-cell transcriptomics showed that lymphatic knockdown attenuated UUO induced intrarenal inflammatory infiltration (from 60% to 25%) and preserved renal tubular epithelial cells (from 40% to 75%). The main reduced inflammatory cells were T cells and DCs. Interestingly, the reduction in T cells included all subpopulations, while the subpopulation reduced in DCs was lymphoid DCs, but not myeloid DCs. The other immune cells, such as macrophages, B cells, and neutrophils, were not altered. In addition, we found that B cells expressed more abundant genes associated with cell senescence such as p21cip1 and p16ink4a after lymphatic knockdown.
Conclusion
We verified that lymphatic knockdown alleviates renal inflammation and fibrosis in UUO kidneys. The decreased immune cells after lymphatic knockdown are T cells and lymphoid DCs, accompanied with B cell senescence, suggesting the adaptive immunity participates in UUO induced renal inflammation and fibrosis.
Funding
- Government Support - Non-U.S.