Abstract: FR-PO1059
Neuropilin-1, the Co-Receptor of TGF-β and TNF-α, Is a Novel Therapeutic Target for Renal Injury and 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
- Li, Yinzheng, 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
- Zeng, Rui, Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Background
Renal fibrosis is the ultimate common pathway of a variety of progressive kidney diseases, in which TGF-β plays an important role. However, current strategies targeting TGF-β showed poor clinical efficacy. One of the reasons for its futility is the co-receptor surrogacy. Neuropilin-1 (NRP1) is a transmembrane glycoprotein acting as a co-receptor of TGF-β and TNF-α, which is recently identified as a potential therapeutic target for pulmonary fibrosis. However, its role in kidney injury and renal fibrosis is unclear.
Methods
Kidney samples from patients with transplanted renal insufficiency and ischemia-reperfusion mice was analyzed. NRP1-KSP mice were generated to deplete NRP1 in renal tubular epithelial cells (TECs). The molecular mechanisms of NRP1 in kidney injury and renal fibrosis were explored via multi-omics analysis of single cell sequencing, transcriptomics and proteomics.
Results
NRP1 expression is upregulated in TECs in transplanted renal insufficiency patients and mice with IR induced AKI, which is co-expressed with receptors of TGF-β or TNF-α. Knockdown of NRP1 in TECs reduced IR-induced kidney injury and fibrosis in mice. NRP1+ distal tubular cells secreted collagen and cytokines, and communicated with myofibroblasts, exacerbating renal fibrosis by activating the SMAD pathway in TECs in a TGF-β receptor dependent manner. Meanwhile, in TGF-β receptor negative distal TECs, NRP1 upregulated TNF-α and its target gene NFKB1 via TNR1A (TNF-α receptor), thereby inhibiting ETV6-related crotonylase expression, which led to downregulation of lysine crotonylation on key glucose metabolic enzymes, exacerbating renal injury, inflammation and fibrosis.
Conclusion
NRP1 is a key molecule promoting kidney injury and fibrosis via activation of SMAD3, TECs-myofibroblasts crosstalk and inhibiting crotonylation of key glucose metabolic enzymes, which promotes the pro-fibrotic and pro-inflammatory effects in both TGF-β receptor negative and positive TECs. Therefore, NRP1 is a novel therapeutic target for kidney disease.
Funding
- Government Support – Non-U.S.