Targeting Neuropilin-1 in Distal Tubules Improves Kidney Injury and Fibrosis

Background: Transforming growth factor-beta (TGF-β) is a critical driver of organ fibrosis, but current strategies to target it are clinically ineffective. One reason for this inefficiency is due to co-receptor surrogacy. Notably, Neuropilin-1 (NRP1), a broad-spectrum co-receptor for various cytokines, has been identified as a potential therapeutic target for liver and pulmonary fibrosis in recent years. However, its role in renal injury and renal fibrosis is still unclear. Therefore, this study aimed to investigate the role of NRP1 in kidney injury and fibrosis and its specific mechanisms. Methods: Renal puncture specimens from patients with transplant renal insufficiency and kidney samples from ischemia-reperfusion (IR) mice were analyzed. Additionally, multi-omics analyses including single-cell RNA sequencing (scRNA-seq), transcriptomics, proteomics, and post-translational modified proteomics were conducted to investigate the role of NRP1 in renal injury and fibrosis. Results: NRP1 expression was found to been upregulated in DT of patients with transplant renal insufficiency and mice with IR injury. Knockdown of NRP1 in DT reduced IR-induced kidney injury and fibrosis in mice. Increased TNF-α after renal injury promoted NFKB1 expression by promoting the binding of NRP1 to TNR1A (TNF-α receptor), thereby inhibiting its downstream target protein ACOX3. The downregulation of ACOX3 lead to a decrease in lysine crotonylation modification level of cytochrome c oxidase subunit COX4, which consequently resulted in mitochondrial damage and a decrease in oxidative phosphorylation level. This lead to increased cell death in DT, ultimately exacerbating renal injury. Meanwhile, NRP1-positive DT secrete collagen and communicate with myofibroblasts, exacerbating renal fibrosis by activating TGF-β-dependent/independent SMAD3 signaling in renal DT. Conclusion: NRP1 worsens renal injury and fibrosis by inhibiting the lysine crotonylation modification level of cytochrome c oxidase subunit COX4 and bi-activation of TGF-β-dependent and -independent SMAD3 signaling. Intervention against NRP1 represents a promising strategy for the treatment of chronic kidney diseases. Funding: Other U.S. Government Support