Uromodulin p.His36Tyr promotes macrophage pyroptosis via App-Cd74 signaling to drive renal inflammation in ADTKD

Uromodulin p.His36Tyr promotes macrophage pyroptosis via App-Cd74 signaling to drive renal inflammation in ADTKD | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Uromodulin p.His36Tyr promotes macrophage pyroptosis via App-Cd74 signaling to drive renal inflammation in ADTKD Bin Wang, Qian-Qian Wu, Si-Qi Peng, Yi-Lin Zhang, Yan Yang, Wen Shi, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7108955/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Autosomal dominant tubulointerstitial kidney disease -UMOD (ADTKD-UMOD) is characterized by progressive renal interstitial inflammation and fibrosis. However, its underlying mechanisms remain unclear. Here, we identify a large ADTKD pedigree harboring a novel UMOD p.H36Y mutation. Using CRISPR/Cas9 technology, we generated a UmodH36Y/+ mouse model that recapitulates the key phenotypes observed in affected individuals, including renal dysfunction, cyst formation, interstitial inflammation, and fibrosis. Multi-omics analyses revealed marked macrophage pyroptosis in UmodH36Y/+ kidneys. Treatment with disulfiram (DSF), a pyroptosis inhibitor, significantly alleviated interstitial inflammation and improved renal function. Mechanistically, the Umod p.H36Y variant activated the amyloid precursor protein (App)-Cd74 axis which mediated the crosstalk between renal TECs and macrophages. This axis sustains NF-κB pathway activation in macrophages, initiating pyroptosis and pro-inflammatory cytokine release. Disrupting App-Cd74 signaling effectively suppressed macrophage pyroptosis. Notably, pharmacologic inhibition using ARN2966, a small-molecule App inhibitor, markedly attenuated renal injury in UmodH36Y/+ mice. Collectively, these findings uncover a novel, targetable pathway in ADTKD-UMOD. Health sciences/Nephrology/Kidney diseases/Interstitial disease Health sciences/Diseases/Kidney diseases/Chronic kidney disease ADTKD-UMOD umod macrophage pyroptosis App-Cd74 signaling treatment Full Text Additional Declarations There is NO Competing Interest. Supplementary Files supplementarymaterials.pdf supplementary materials Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7108955","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":488460902,"identity":"efc5a662-b3f6-421a-9cf1-ee274817f70e","order_by":0,"name":"Bin Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIie3PMQrCMBTG8QeBugRcK0LP8CBQBAWv0iJkCrXgBTyA4JpjeAMtD3VRXAsVHAQXHQIuDoJWnVwa3QTznxL4foQAuFw/GgOE6HGYGewE35FMp1J8SOBFGDcUW+e4XNMxTbdJ3e9l1EEWQY3mk0qySmRb42HQ0DIihV4CXMq8ioQzFQqOFE8KhSXhA/B5WE02pxeZFn1DLfTjoZXkSuyfrzQVECDaSTc/hUyXRO8OmI0wEp7tL42xEuf0SvF4RHtzud6Ceo0WlaTM89+vlvkjZj4YuVwu1z93ByEHUIReviJmAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-1606-5004","institution":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Bin","middleName":"","lastName":"Wang","suffix":""},{"id":488460903,"identity":"01c61ee3-5022-47aa-88d2-59832e1c765d","order_by":1,"name":"Qian-Qian Wu","email":"","orcid":"","institution":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Qian-Qian","middleName":"","lastName":"Wu","suffix":""},{"id":488460904,"identity":"1c3badfa-736c-4edd-ac91-e9eae02e9e8f","order_by":2,"name":"Si-Qi Peng","email":"","orcid":"","institution":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Si-Qi","middleName":"","lastName":"Peng","suffix":""},{"id":488460905,"identity":"738d8222-4900-40e7-946e-b0499fa6e169","order_by":3,"name":"Yi-Lin Zhang","email":"","orcid":"","institution":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yi-Lin","middleName":"","lastName":"Zhang","suffix":""},{"id":488460906,"identity":"63d10c41-ac3e-4db7-9156-18699b4bb84c","order_by":4,"name":"Yan Yang","email":"","orcid":"","institution":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Yang","suffix":""},{"id":488460907,"identity":"8f8e45d3-cf27-4713-91ee-4712898eb07b","order_by":5,"name":"Wen Shi","email":"","orcid":"","institution":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Wen","middleName":"","lastName":"Shi","suffix":""},{"id":488460908,"identity":"c334492a-b909-4a0b-b737-d9174a10b2b1","order_by":6,"name":"Xian-Li Wen","email":"","orcid":"","institution":"Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xian-Li","middleName":"","lastName":"Wen","suffix":""},{"id":488460909,"identity":"977a97e9-9544-432a-b680-9dab331932f1","order_by":7,"name":"Zhi-Ying Liu","email":"","orcid":"","institution":"Renal Division, Peking University First Hospital, Peking University Institute of Nephrology","correspondingAuthor":false,"prefix":"","firstName":"Zhi-Ying","middleName":"","lastName":"Liu","suffix":""},{"id":488460910,"identity":"de6f7685-6609-491f-aa1b-f01161d58122","order_by":8,"name":"Xu-Jie Zhou","email":"","orcid":"","institution":"Renal Division, Peking University First Hospital, Peking University Institute of Nephrology","correspondingAuthor":false,"prefix":"","firstName":"Xu-Jie","middleName":"","lastName":"Zhou","suffix":""},{"id":488460911,"identity":"208eb0f9-83d6-4224-9c1b-dcc10a6bdfee","order_by":9,"name":"Mingzhu Zheng","email":"","orcid":"","institution":"Department of Microbiology and Immunology, School of Medicine, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Southeast University, Nanjing, Jiangsu 210009, China.","correspondingAuthor":false,"prefix":"","firstName":"Mingzhu","middleName":"","lastName":"Zheng","suffix":""},{"id":488460912,"identity":"304d858f-2bc7-4b96-a74b-de61134b840f","order_by":10,"name":"Lidan Hu","email":"","orcid":"","institution":"Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Lidan","middleName":"","lastName":"Hu","suffix":""},{"id":488460913,"identity":"bce4ac41-e984-4f04-817d-984828e1dbfc","order_by":11,"name":"Xiao-Min Li","email":"","orcid":"","institution":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xiao-Min","middleName":"","lastName":"Li","suffix":""},{"id":488460914,"identity":"674be611-0630-4ddb-81f7-e02528eb362c","order_by":12,"name":"Jing-Yuan Cao","email":"","orcid":"","institution":"Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jing-Yuan","middleName":"","lastName":"Cao","suffix":""},{"id":488460915,"identity":"0c3f145c-587b-4485-a888-491385e402ac","order_by":13,"name":"Xin-Lu Wang","email":"","orcid":"","institution":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xin-Lu","middleName":"","lastName":"Wang","suffix":""},{"id":488460916,"identity":"7431ac22-43f2-4996-98fd-1e25d7212221","order_by":14,"name":"Jun-Lan Yang","email":"","orcid":"","institution":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jun-Lan","middleName":"","lastName":"Yang","suffix":""},{"id":488460917,"identity":"3133485a-b8d8-4f01-8208-1a28848a0264","order_by":15,"name":"Jin-Xuan Wei","email":"","orcid":"","institution":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jin-Xuan","middleName":"","lastName":"Wei","suffix":""},{"id":488460918,"identity":"1ddc61df-4019-445e-ad2d-940f3db6f13a","order_by":16,"name":"Jun-Yuan Shen","email":"","orcid":"","institution":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jun-Yuan","middleName":"","lastName":"Shen","suffix":""},{"id":488460919,"identity":"f19e8d16-4d00-4673-b5b2-badd11155c69","order_by":17,"name":"Xiao-Xu Wang","email":"","orcid":"","institution":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xiao-Xu","middleName":"","lastName":"Wang","suffix":""},{"id":488460920,"identity":"96e83745-ade2-4936-a8d0-75d1e1eb4465","order_by":18,"name":"Bi-Cheng Liu","email":"","orcid":"https://orcid.org/0000-0002-4584-1853","institution":"Southeast University","correspondingAuthor":false,"prefix":"","firstName":"Bi-Cheng","middleName":"","lastName":"Liu","suffix":""},{"id":488460921,"identity":"d04b2139-d4c5-472b-bc47-0d921d3bbac4","order_by":19,"name":"Xiaoliang Zhang","email":"","orcid":"","institution":"Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xiaoliang","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-07-12 15:15:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7108955/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7108955/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87277014,"identity":"cfa1e66c-981b-44f3-a9f0-86e2f9bbc8eb","added_by":"auto","created_at":"2025-07-22 09:11:14","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":21900270,"visible":true,"origin":"","legend":"Article File","description":"","filename":"CombinedPDF.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7108955/v1_covered_4a2384a0-1ede-4b2f-8d04-973df2ec7609.pdf"},{"id":87275791,"identity":"281cb0ff-9021-4f81-8129-831bda42ecdd","added_by":"auto","created_at":"2025-07-22 09:03:02","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2751973,"visible":true,"origin":"","legend":"supplementary materials","description":"","filename":"supplementarymaterials.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7108955/v1/a51c710b68a0ec97a3596bee.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Uromodulin p.His36Tyr promotes macrophage pyroptosis via App-Cd74 signaling to drive renal inflammation in ADTKD","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"ADTKD-UMOD, umod, macrophage pyroptosis, App-Cd74 signaling, treatment","lastPublishedDoi":"10.21203/rs.3.rs-7108955/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7108955/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Autosomal dominant tubulointerstitial kidney disease -UMOD (ADTKD-UMOD) is characterized by progressive renal interstitial inflammation and fibrosis. However, its underlying mechanisms remain unclear. Here, we identify a large ADTKD pedigree harboring a novel UMOD p.H36Y mutation. Using CRISPR/Cas9 technology, we generated a UmodH36Y/+ mouse model that recapitulates the key phenotypes observed in affected individuals, including renal dysfunction, cyst formation, interstitial inflammation, and fibrosis. Multi-omics analyses revealed marked macrophage pyroptosis in UmodH36Y/+ kidneys. Treatment with disulfiram (DSF), a pyroptosis inhibitor, significantly alleviated interstitial inflammation and improved renal function. Mechanistically, the Umod p.H36Y variant activated the amyloid precursor protein (App)-Cd74 axis which mediated the crosstalk between renal TECs and macrophages. This axis sustains NF-κB pathway activation in macrophages, initiating pyroptosis and pro-inflammatory cytokine release. Disrupting App-Cd74 signaling effectively suppressed macrophage pyroptosis. Notably, pharmacologic inhibition using ARN2966, a small-molecule App inhibitor, markedly attenuated renal injury in UmodH36Y/+ mice. Collectively, these findings uncover a novel, targetable pathway in ADTKD-UMOD.","manuscriptTitle":"Uromodulin p.His36Tyr promotes macrophage pyroptosis via App-Cd74 signaling to drive renal inflammation in ADTKD","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-22 09:02:57","doi":"10.21203/rs.3.rs-7108955/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8602f1aa-822b-43d8-aae8-73e88bd7e9f2","owner":[],"postedDate":"July 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":51849904,"name":"Health sciences/Nephrology/Kidney diseases/Interstitial disease"},{"id":51849905,"name":"Health sciences/Diseases/Kidney diseases/Chronic kidney disease"}],"tags":[],"updatedAt":"2026-04-15T08:28:48+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-22 09:02:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7108955","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7108955","identity":"rs-7108955","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}