PDF(Pubmed)
Abstract：
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.
摘要：
Neuropilin-1(NRP1),各种细胞因子的共受体，包括TGF-β,已被确定为纤维化的潜在治疗靶标。然而,其在肾纤维化中的作用和机制仍然难以捉摸。这里,我们显示，NRP1在移植肾功能不全患者和肾缺血再灌注（I-R）损伤小鼠的远端肾小管（DT）细胞中上调。Nrp1基因敲除减少肾损伤和纤维化的多个终点。我们发现Nrp1促进肾损伤后DT细胞中TNF-α与其受体的结合。该信号导致代谢酶Cox4i1的赖氨酸巴豆化的下调，降低细胞能量并加重肾损伤。此外，通过单细胞RNA测序，我们发现Nrp1阳性DT细胞分泌胶原蛋白并与肌成纤维细胞交流，通过激活Smad3加重急性肾损伤（AKI）诱导的肾纤维化。DT细胞中Nrp1和Tgfbr1的双重遗传缺失比任一单一敲除都能更好地改善肾损伤和纤维化。一起,这些结果表明,靶向NRP1是治疗AKI和随后的慢性肾脏病的有希望的策略.
