AbstractNatriuretic peptides (NPs) are cardio-derived hormones that have a crucial role in maintaining cardiovascular homeostasis. Physiological effects of NPs are mediated by binding to natriuretic peptide receptors 1 and 2 (NPR1/2), whereas natriuretic peptide receptor 3 (NPR3) acts as a clearance receptor that removes NPs from the circulation.

摘要利钠肽（NPs）是心脏衍生的激素，在维持心血管稳态中起着至关重要的作用。NPs的生理作用是通过与利钠肽受体1和2（NPR1/2）结合来介导的，而利钠肽受体3（NPR3）充当清除受体，从循环中去除NPs。

Mouse studies have shown that local NP-signaling in the kidney glomerulus is important for the maintenance of renal homeostasis. In this study we examined the expression of NPR3 in kidney tissue and explored its involvement in renal physiology and disease by generating podocyte-specific knockout mice (NPR3podKO) as well as by using an NPR3 inhibitor (NPR3i) in rodent models of kidney disease.

小鼠研究表明，肾小球中的局部NP信号传导对于维持肾脏稳态很重要。在这项研究中，我们通过产生足细胞特异性敲除小鼠（NPR3podKO）以及在肾脏疾病的啮齿动物模型中使用NPR3抑制剂（NPR3i），检测了NPR3在肾脏组织中的表达，并探讨了其在肾脏生理和疾病中的作用。

NPR3 was highly expressed by podocytes. NPR3podKO animals showed no renal abnormalities under healthy conditions and responded similarly to nephrotoxic serum (NTS) induced glomerular injury. However, NPR3i showed reno-protective effects in the NTS-induced model evidenced by decreased glomerulosclerosis and reduced podocyte loss.

NPR3由足细胞高度表达。NPR3podKO动物在健康条件下未显示肾脏异常，并且对肾毒性血清（NTS）诱导的肾小球损伤的反应相似。然而，NPR3i在NTS诱导的模型中显示出肾脏保护作用，这可以通过减少肾小球硬化和减少足细胞损失来证明。

In a ZSF1 rat model of diabetic kidney injury, therapy alone with NPR3i did not have beneficial effects on renal function/histology, but when combined with losartan (angiotensin receptor blocker), NPR3i potentiated its ameliorative effects on albuminuria. In conclusion, these results suggest that NPR3 may contribute to kidney disease progression.

在糖尿病肾损伤的ZSF1大鼠模型中，单独使用NPR3i对肾功能/组织学没有有益作用，但当与氯沙坦（血管紧张素受体阻滞剂）联合使用时，NPR3i增强了其对白蛋白尿的改善作用。总之，这些结果表明NPR3可能有助于肾脏疾病的进展。

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IntroductionRenal glomerular disease processes are the most common cause of chronic kidney disease (CKD) affecting millions of people worldwide1. Podocytes, endothelial cells, and mesangial cells are the principal glomerular cell types. They play a unique and specialized role in the maintenance of normal physiology, as well as are the main targets of injury in many forms of CKD2.

引言肾小球疾病过程是影响全球数百万人的慢性肾病（CKD）的最常见原因1。足细胞，内皮细胞和系膜细胞是主要的肾小球细胞类型。它们在维持正常生理方面发挥着独特而专业的作用，也是许多形式的CKD2损伤的主要目标。

Today, glomerulopathies are treated with drugs that do not target specific glomerular disease mechanisms but are believed to have indirect reno-protective effects (such as via blood pressure).Natriuretic peptides (NPs) are a family of hormones/paracrine factors that interact with their receptors; a family of peptide binding proteins called natriuretic peptide receptors (NPRs).

今天，肾小球疾病的治疗药物不针对特定的肾小球疾病机制，但被认为具有间接的肾脏保护作用（例如通过血压）。利钠肽（NPs）是与其受体相互作用的激素/旁分泌因子家族；称为利钠肽受体（NPR）的肽结合蛋白家族。

Most of the physiological effects of NPs have been attributed to NPR1 (NPRA) or NPR2 (NPRB), which, upon NP binding, catalyze the synthesis of intracellular cyclic-GMP (cGMP), a major down-stream effector of NP-signaling pathway. The third member of this receptor family, NPR3 (NPRC), lacks the intracellular signaling domain and acts as a clearance receptor that removes NPs from the circulation and thus suppresses the pathway3.In the glomerulus, NPR1 is highly expressed by podocytes.

NPs的大多数生理作用归因于NPR1（NPRA）或NPR2（NPRB），NPR1（NPRA）或NPR2（NPRB）在NP结合后催化细胞内环GMP（cGMP）的合成，cGMP是NP信号通路的主要下游效应子。该受体家族的第三个成员NPR3（NPRC）缺乏细胞内信号传导结构域，并作为清除受体，从循环中去除NPs，从而抑制通路3。在肾小球中，NPR1由足细胞高度表达。

Inactivation of NPR1 specifically in podocytes does not affect systemic NP levels or result in renal disease. However, under pathological conditions, the absence of NPR1 in podocytes promotes glomerular damage, suggesting that local NP signaling in the glomerulus contributes to renal protection4. In addition, a significant downregulation of NPR1 and NPR3 has been observed in the glomerular tissue of diabetic nephropathy (DN) patients5.

足细胞中NPR1的特异性失活不会影响全身NP水平或导致肾脏疾病。然而，在病理条件下，足细胞中NPR1的缺失会促进肾小球损伤，这表明肾小球中的局部NP信号传导有助于肾脏保护4。此外，在糖尿病肾病（DN）患者的肾小球组织中观察到NPR1和NPR3的显着下调5。

Meanwhile, NPR3 was reported to suppress NPR1-cGMP signaling in heart fibrosis and to enhance the response to.

同时，据报道NPR3抑制心脏纤维化中的NPR1-cGMP信号传导并增强对的反应。

Data availability

数据可用性

All data generated or anlysed during this study are included in this published article (and its supplementary information files).

本研究期间生成或分析的所有数据均包含在本文（及其补充信息文件）中。

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Download referencesFundingOpen access funding provided by Karolinska Institute.Author informationAuthor notesThese authors contributed equally: Dina Dabaghie and Emmanuelle Charrin.Authors and AffiliationsDivision of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, SwedenDina Dabaghie, Emmanuelle Charrin, Gizem Korkut & Jaakko PatrakkaBioscience Renal, Cardiovascular, Renal and Metabolism (CVRM), R&D Biopharmaceuticals, AstraZeneca, Gothenburg, SwedenPernilla Tonelius, Birgitta Rosengren, Anna B.

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PubMed Google ScholarContributionsDD, EC, ML and JP designed the study. DD and EC performed all mouse experiments. PT, BR and ABR performed rat experiments. GK performed part of tissue analyses and revised the manuscript. ML and ML supervised the analysis of the data. DD and EC wrote the first draft of the manuscript, all other authors revised and accepted the final version.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献SDD，EC，ML和JP设计了这项研究。DD和EC进行了所有小鼠实验。PT，BR和ABR进行了大鼠实验。GK进行了部分组织分析并修改了手稿。ML和ML监督了数据的分析。DD和EC撰写了手稿的初稿，所有其他作者都修改并接受了最终版本。对应作者对应。

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Competing interests

相互竞争的利益

EC, PT, BR, ABG and ML are/were employed by AstraZeneca. JP’s research lab is financially supported by AstraZeneca. JP is employed by Unilabs. All other authors have no competing interest.

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Reprints and permissionsAbout this articleCite this articleDabaghie, D., Charrin, E., Tonelius, P. et al. Unraveling the role of natriuretic peptide clearance receptor (NPR3) in glomerular diseases.

转载和许可本文引用本文Dabaghie，D.，Charrin，E.，Tonelius，P。等人揭示了利钠肽清除受体（NPR3）在肾小球疾病中的作用。

Sci Rep 14, 11850 (2024). https://doi.org/10.1038/s41598-024-61603-4Download citationReceived: 04 November 2023Accepted: 07 May 2024Published: 24 May 2024DOI: https://doi.org/10.1038/s41598-024-61603-4Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Sci Rep 1411850（2024）。https://doi.org/10.1038/s41598-024-61603-4Download引文接收日期：2023年11月4日接收日期：2024年5月7日发布日期：2024年5月24日OI：https://doi.org/10.1038/s41598-024-61603-4Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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