Abstract: FR-PO1046
Immunomodulatory and Metabolic Adaptation in Transcriptional Signature After Knockdown of Proliferating Lymphatic Vessels in Mice with Renal Fibrosis
Session Information
- CKD Mechanisms: Progression, Fibrosis, and Beyond
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Wang, Zheng, Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hu, Danni, Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Pei, Guangchang, Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Yao, Ying, Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Xu, Gang, Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Zeng, Rui, Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Background
Our previous study has reported that renal lymphangiogenesis accelerates the progression of chronic kidney disease (CKD). However, it is not clear which immune cell types drive renal outcome.
Methods
We established the selective proliferating lymphatic vessel knockout mice for unilateral ureteral obstruction (UUO)-induced fibrosis. Bulk RNA sequencing and single-cell RNA sequencing were used to characterize changes in the transcriptional profiles of renal parenchymal and immune cell following the knocking down of lymphatic vessels (LVs).
Results
The fibrosis were alleviated following knockdown of LVs. Bulk RNA sequencing showed that the impaired secretion of cytokines and chemokines, and impaired energy metabolism were improved. Single-cell RNA sequencing confirmed that the decreased proportion of epithelial cells was restored, and the immune cells aggregation (especially NK cells and T lymphocytes) was dissipated. Three subpopulations of NK cells were identified: NK1, characterized as CD27+CD11b+ NK cells that primarily facilitate the migration of myeloid immune cells, was enhanced; NK2, characterized as CD27+CD11b- NK cells that mainly stimulate the differentiation of lymphoid immune cells, was increased; and NK3, characterized as CD27-CD11b+ NK cells that function as pro-inflammatory cells, was significantly decreased. Ten subpopulations of T lymphocytes were identified: the proportion of CD8+T, CD4+ T, γδT, NKT, IFN-related T, effector memory T, and Tregs were increased, serving mainly to promote immunity cell activation, while the proportion of proliferative T, Th17, and naïve CD8+T, that mainly promoting the migration of immune cells, were significantly decreased. Subsequently, stromal cells and their extra-cellular matrix (ECM) production capacity decreased following LV knockdown. Additionally, the LVs knockdown caused an attenuation of G2/M arrest and programmed death in injured tubular epithelial cells (TECs) while restoring fatty acid oxidation and gluconeogenesis.
Conclusion
Knocking down of proliferating LVs improve the inflammatory immune microenvironment via the regulation of NK and T cells, and then inhibit stromal cells to produce ECM and restore the energy metabolism of TECs, which suggest proliferating LVs is a potential therapeutic target for renal fibrosis.
Funding
- Government Support – Non-U.S.