Renal nerve stimulation modulates renal blood flow in a frequency-dependent manner

Renal nerve stimulation modulates renal blood flow in a frequency-dependent manner | 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 Research Article Renal nerve stimulation modulates renal blood flow in a frequency-dependent manner Dzifa Kwaku, Dusty Helden, Joan Dao, John Osborn, Matthew D. Johnson This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7724105/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Nov, 2025 Read the published version in Bioelectronic Medicine → Version 1 posted 11 You are reading this latest preprint version Abstract Background Chronic overactivity of the renal nerves is a key pathophysiological attribute of drug-resistant hypertension. Indeed, catheter-based renal denervation can lower blood pressure by severing the brain-kidney (efferent nerves) and kidney-brain (afferent nerves) link, but its irreversibility and potential nerve reconnection limits adaptability and longevity, highlighting the need for alternative treatments. Kilohertz-frequency electrical stimulation is an approach known to reversibly inhibit peripheral nerve activity and has potential to reversibly modulate renal blood flow. Methods This study investigated how electrical stimulation of the renal nerves affects renal blood flow in a non-diseased anesthetized swine. Using unilateral hook electrodes around the renal artery complex, we performed parameter sweeps of stimulation frequency (20 -15000 Hz) and measured blood flow and blood pressure changes in the ipsilateral kidney. Results Stimulation at low frequencies (≤ 100 Hz) resulted in a sustained reduction in renal blood flow. High stimulation frequencies (> 100 Hz) often resulted in an immediate decrease in blood flow through the kidneys, but the responses exhibited adaptation with continued isochronal pulsatile stimulation. Notably, while kilohertz-frequency stimulation did not directly increase renal blood flow in this experiment, it did induce a carryover effect on renal nerve sensitivities to low-frequency stimulation, reducing the effect of subsequent low-frequency stimulation on renal blood flow (from − 11.8% to -4.7%, median). Conclusions Responses to renal nerve stimulation depend on stimulation frequency with effects that can persist or adapt as well as effects that can range from decreasing renal blood flow to decreasing the sensitivity of the renal nerve signaling pathway. These findings have important implications for future development of bioelectronic interfaces with the renal nerve for modulation of kidney function. renal nerve renal blood flow peripheral nerve stimulation kilohertz-frequency stimulation blood pressure hypertension Full Text Additional Declarations No competing interests reported. Supplementary Files Supplementaryfigures.docx Cite Share Download PDF Status: Published Journal Publication published 29 Nov, 2025 Read the published version in Bioelectronic Medicine → Version 1 posted Editorial decision: Revision requested 14 Oct, 2025 Reviews received at journal 14 Oct, 2025 Reviews received at journal 09 Oct, 2025 Reviewers agreed at journal 08 Oct, 2025 Reviewers agreed at journal 04 Oct, 2025 Reviewers agreed at journal 03 Oct, 2025 Reviewers agreed at journal 01 Oct, 2025 Reviewers invited by journal 01 Oct, 2025 Editor assigned by journal 30 Sep, 2025 Submission checks completed at journal 28 Sep, 2025 First submitted to journal 26 Sep, 2025 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. 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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-7724105","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":528046078,"identity":"810f54af-6b9e-4778-baa2-06fb91eec20b","order_by":0,"name":"Dzifa Kwaku","email":"","orcid":"","institution":"University of Minnesota","correspondingAuthor":false,"prefix":"","firstName":"Dzifa","middleName":"","lastName":"Kwaku","suffix":""},{"id":528046079,"identity":"fc55124d-6d8a-408a-ba74-977f1f0c6863","order_by":1,"name":"Dusty Helden","email":"","orcid":"","institution":"University of Minnesota","correspondingAuthor":false,"prefix":"","firstName":"Dusty","middleName":"","lastName":"Helden","suffix":""},{"id":528046080,"identity":"f52fb082-5dc0-4ecb-8416-3edc86976274","order_by":2,"name":"Joan Dao","email":"","orcid":"","institution":"University of Minnesota","correspondingAuthor":false,"prefix":"","firstName":"Joan","middleName":"","lastName":"Dao","suffix":""},{"id":528046081,"identity":"a38be4f2-7d39-4c55-9b15-464710c1c226","order_by":3,"name":"John Osborn","email":"","orcid":"","institution":"University of Minnesota","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"","lastName":"Osborn","suffix":""},{"id":528046082,"identity":"79e5bede-7684-4c23-987b-229481b79157","order_by":4,"name":"Matthew D. 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manner","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"bioelectronic-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"beme","sideBox":"Learn more about [Bioelectronic Medicine](https://bioelecmed.biomedcentral.com)","snPcode":"42234","submissionUrl":"https://submission.springernature.com/new-submission/42234/3","title":"Bioelectronic Medicine","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"renal nerve, renal blood flow, peripheral nerve stimulation, kilohertz-frequency stimulation, blood pressure, hypertension","lastPublishedDoi":"10.21203/rs.3.rs-7724105/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7724105/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eChronic overactivity of the renal nerves is a key pathophysiological attribute of drug-resistant hypertension. Indeed, catheter-based renal denervation can lower blood pressure by severing the brain-kidney (efferent nerves) and kidney-brain (afferent nerves) link, but its irreversibility and potential nerve reconnection limits adaptability and longevity, highlighting the need for alternative treatments. Kilohertz-frequency electrical stimulation is an approach known to reversibly inhibit peripheral nerve activity and has potential to reversibly modulate renal blood flow.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis study investigated how electrical stimulation of the renal nerves affects renal blood flow in a non-diseased anesthetized swine. Using unilateral hook electrodes around the renal artery complex, we performed parameter sweeps of stimulation frequency (20 -15000 Hz) and measured blood flow and blood pressure changes in the ipsilateral kidney.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eStimulation at low frequencies (\u0026le;\u0026thinsp;100 Hz) resulted in a sustained reduction in renal blood flow. High stimulation frequencies (\u0026gt;\u0026thinsp;100 Hz) often resulted in an immediate decrease in blood flow through the kidneys, but the responses exhibited adaptation with continued isochronal pulsatile stimulation. Notably, while kilohertz-frequency stimulation did not directly increase renal blood flow in this experiment, it did induce a carryover effect on renal nerve sensitivities to low-frequency stimulation, reducing the effect of subsequent low-frequency stimulation on renal blood flow (from \u0026minus;\u0026thinsp;11.8% to -4.7%, median).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eResponses to renal nerve stimulation depend on stimulation frequency with effects that can persist or adapt as well as effects that can range from decreasing renal blood flow to decreasing the sensitivity of the renal nerve signaling pathway. These findings have important implications for future development of bioelectronic interfaces with the renal nerve for modulation of kidney function.\u003c/p\u003e","manuscriptTitle":"Renal nerve stimulation modulates renal blood flow in a frequency-dependent manner","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-14 01:32:08","doi":"10.21203/rs.3.rs-7724105/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-14T11:37:06+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-14T11:08:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-09T09:19:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"293505394628325418380047898513857702178","date":"2025-10-08T13:46:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"209088188216120042602079427723653285205","date":"2025-10-04T20:11:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"301621665945172170673672215850133572948","date":"2025-10-03T11:53:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"13362203185333310966582904245143432383","date":"2025-10-01T11:36:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-01T10:25:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-30T18:22:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-29T00:11:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bioelectronic Medicine","date":"2025-09-26T17:55:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bioelectronic-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"beme","sideBox":"Learn more about [Bioelectronic Medicine](https://bioelecmed.biomedcentral.com)","snPcode":"42234","submissionUrl":"https://submission.springernature.com/new-submission/42234/3","title":"Bioelectronic Medicine","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ee4773ec-ef77-43b5-8267-9160de21dff6","owner":[],"postedDate":"October 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-01T16:02:27+00:00","versionOfRecord":{"articleIdentity":"rs-7724105","link":"https://doi.org/10.1186/s42234-025-00192-7","journal":{"identity":"bioelectronic-medicine","isVorOnly":false,"title":"Bioelectronic Medicine"},"publishedOn":"2025-11-29 15:57:12","publishedOnDateReadable":"November 29th, 2025"},"versionCreatedAt":"2025-10-14 01:32:08","video":"","vorDoi":"10.1186/s42234-025-00192-7","vorDoiUrl":"https://doi.org/10.1186/s42234-025-00192-7","workflowStages":[]},"version":"v1","identity":"rs-7724105","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7724105","identity":"rs-7724105","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}