Targeting the transmembrane cytokine co-receptor neuropilin-1 in distal tubules improves renal injury and fibrosis

• Published in: Nature communications 2024-07, Vol.15 (1), p.5731-18, Article 5731
• Main Authors: Li, Yinzheng, Wang, Zheng, Xu, Huzi, Hong, Yu, Shi, Mengxia, Hu, Bin, Wang, Xiuru, Ma, Shulin, Wang, Meng, Cao, Chujin, Zhu, Han, Hu, Danni, Xu, Chang, Lin, Yanping, Xu, Gang, Yao, Ying, Zeng, Rui
• Format: Article
• Language: English
• Subjects: 13/2; 38; 38/77; 49; 49/91; 692/4022/1585/104; 692/4022/1585/4; 692/499; 82/1; 82/81; Acute Kidney Injury - genetics; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Animals; Clonal deletion; Collagen - metabolism; Cytokines; Distal tubules; Down-regulation; Fibrosis; Gene sequencing; Humanities and Social Sciences; Humans; Injuries; Ischemia; Kidney diseases; Kidney transplantation; Kidney Tubules - metabolism; Kidney Tubules - pathology; Kidneys; Lysine; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Myofibroblasts - metabolism; Myofibroblasts - pathology; Neuropilin; Neuropilin-1 - genetics; Neuropilin-1 - metabolism; Quality of life; Receptor, Transforming Growth Factor-beta Type I - genetics; Receptor, Transforming Growth Factor-beta Type I - metabolism; Receptors; Renal insufficiency; Reperfusion; Reperfusion Injury - genetics; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Science; Science (multidisciplinary); Signal Transduction; Smad3 protein; Smad3 Protein - genetics; Smad3 Protein - metabolism; Therapeutic targets; Transforming growth factor-b; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50121-6

Neuropilin-1 (NRP1), a co-receptor for various cytokines, including TGF-β, has been identified as a potential therapeutic target for fibrosis. However, its role and mechanism in renal fibrosis remains elusive. Here, we show that NRP1 is upregulated in distal tubular (DT) cells of patients with transplant renal insufficiency and mice with renal ischemia-reperfusion (I-R) injury. Knockout of Nrp1 reduces multiple endpoints of renal injury and fibrosis. We find that Nrp1 facilitates the binding of TNF-α to its receptor in DT cells after renal injury. This signaling results in a downregulation of lysine crotonylation of the metabolic enzyme Cox4i1, decreases cellular energetics and exacerbation of renal injury. Furthermore, by single-cell RNA-sequencing we find that Nrp1 -positive DT cells secrete collagen and communicate with myofibroblasts, exacerbating acute kidney injury (AKI)-induced renal fibrosis by activating Smad3. Dual genetic deletion of Nrp1 and Tgfbr1 in DT cells better improves renal injury and fibrosis than either single knockout. Together, these results reveal that targeting of NRP1 represents a promising strategy for the treatment of AKI and subsequent chronic kidney disease. Many studies have shown that progressive human kidney disease seriously affects the quality of life of patients and may lead to their death. Here, the authors show that targeting of NRP1 represents a promising strategy for the treatment of kidney injury and subsequent chronic kidney disease.