{"id":4985,"date":"2024-10-09T17:54:17","date_gmt":"2024-10-09T17:54:17","guid":{"rendered":"https:\/\/medicalaffairs.travere.com\/?post_type=publication&#038;p=4985"},"modified":"2025-09-30T23:51:53","modified_gmt":"2025-09-30T23:51:53","slug":"sparsentan-ameliorates-glomerular-hypercellularity-and-inflammatory-gene-networks-iga-nephropathy-mouse-model","status":"publish","type":"publication","link":"https:\/\/clleancode.top\/travere-redesign\/publications\/sparsentan-ameliorates-glomerular-hypercellularity-and-inflammatory-gene-networks-iga-nephropathy-mouse-model\/","title":{"rendered":"Sparsentan Ameliorates Glomerular Hypercellularity and Inflammatory-gene Networks Induced by IgA1-IgA Immune Complexes in a Mouse Model of IgA Nephropathy"},"content":{"rendered":"\n\n\n\n<section class=\"o-hero-section o-hero--banner o-hero--blue o-hero--cropped\">\n    <img decoding=\"async\" width=\"1920\" height=\"1080\" src=\"https:\/\/clleancode.top\/travere-redesign\/wp-content\/uploads\/2024\/09\/three-mice_header.png\" class=\"a-img a-img--right h-full\" alt=\"Hero Section Background Image\" loading=\"lazy\" srcset=\"https:\/\/clleancode.top\/travere-redesign\/wp-content\/uploads\/2024\/09\/three-mice_header.png 1920w, https:\/\/clleancode.top\/travere-redesign\/wp-content\/uploads\/2024\/09\/three-mice_header-300x169.webp 300w, https:\/\/clleancode.top\/travere-redesign\/wp-content\/uploads\/2024\/09\/three-mice_header-1024x576.webp 1024w, https:\/\/clleancode.top\/travere-redesign\/wp-content\/uploads\/2024\/09\/three-mice_header-768x432.webp 768w, https:\/\/clleancode.top\/travere-redesign\/wp-content\/uploads\/2024\/09\/three-mice_header-1536x864.webp 1536w, https:\/\/clleancode.top\/travere-redesign\/wp-content\/uploads\/2024\/09\/three-mice_header-290x163.webp 290w\" sizes=\"auto, (max-width: 1920px) 100vw, 1920px\" \/>    <div class=\"container\">\n        <div class=\"m-hero-inner m-hero-inner--post\">\n            <div class=\"m-breadcrumb\">\n                <nav class=\"breadcrumbs\" aria-label=\"breadcrumb\"><span><span><a href=\"https:\/\/clleancode.top\/travere-redesign\/\">Home<\/a><\/span><\/span><\/nav>            <\/div>\n            <h1 class=\"a-heading a-heading--h1 h-white\">Sparsentan Ameliorates Glomerular Hypercellularity and Inflammatory-Gene Networks Induced by IgA1-IgG Immune Complexes in a Mouse Model of IgA Nephropathy<\/h1>                    <\/div>\n    <\/div>\n<\/section>\n\n\r\n\t<section style=\"margin-top:calc(-150px * var(--scale));\" class=\"section-container wp-block-grizzly-section-container\">\r\n\t\t\t\t<div class=\"container\">\r\n\t\t\t\n\n<div class=\"wp-block-group is-layout-constrained wp-container-core-group-is-layout-09ab29e6 wp-block-group-is-layout-constrained\">\n<div class=\"info-block info-block-publication search__container-publication search__container\">\n\t<div class=\"info-block-top\">\n\t\t<div>\n\t\t\t\t\t\t\t<div class=\"info-block-type\"><i class=\"icon2-journal\"><\/i> Journal article<\/div>\n\t\t\t\n\t\t\t\t\t\t\t<div class=\"info-block-type\">\n\t\t\t\t\t<i class=\"icon2-calendar\"><\/i> Published on March 21, 2024\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\n\t\t\t\t\t<div class=\"m-tags\">\n\t\t\t\t<p>Topics: <\/p>\n\t\t\t\t\t\t\t\t\t<span class=\"a-tag\">Nephrology<\/span>\n\t\t\t\t\t\t\t\t\t<span class=\"a-tag\">IgAN<\/span>\n\t\t\t\t\t\t\t<\/div>\n\t\t\t<\/div>\n\n\t<div class=\"info-block-bottom\">\n\t\t\t\t\t<div class=\"info-block-box\">\n\t\t\t\tContributors:<br \/><span>Reily C, Moldoveanu Z, Pramparo T et al.<\/span>\n\t\t\t<\/div>\n\t\t\n\t\t<div class=\"info-block-box\">\n\t\t\t\t\t\t\tName of Journal:<br \/><span>American Journal of Renal Physiology<\/span><br \/><br \/><br \/>\n\t\t\t\n\t\t\t\t\t\t\t<a href=\"#\" data-url=\"https:\/\/journals.physiology.org\/doi\/full\/10.1152\/ajprenal.00253.2023\" target=\"_blank\" 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For more information, review the <a href=\"https:\/\/travere.com\/privacy\/\" target=\"_blank\">Travere privacy policies<\/a>.<\/span><\/label><\/span><\/span><\/span>\n  <\/div>\n  <div class=\"form-group text-right\">\n    <input class=\"wpcf7-form-control wpcf7-submit has-spinner btn\" id=\"request-submit\" type=\"submit\" value=\"Yes, continue\" \/>\n  <\/div>\n<\/div><div class=\"wpcf7-response-output\" aria-hidden=\"true\"><\/div>\n<\/form>\n<\/div>\n\t\t<\/div>\n\t<\/div>\n<\/div> <\/div>\n\n\t\t<\/div>\r\n\t<\/section>\r\n\t\n\n\r\n\t<section class=\"section-container wp-block-grizzly-section-container\">\r\n\t\t\t\t<div class=\"container\">\r\n\t\t\t\n\n<div class=\"wp-block-group is-layout-constrained wp-container-core-group-is-layout-09ab29e6 wp-block-group-is-layout-constrained\">\n<h2 class=\"wp-block-heading has-text-align-center has-heading-4-font-size\" id=\"h-summary\" style=\"margin-top:calc(60px * var(--scale));margin-bottom:calc(30px * var(--scale))\"><span class=\"fw-600\"><mark style=\"background-color:rgba(0, 0, 0, 0)\" class=\"has-inline-color has-teal-color\">Summary<\/mark><\/span><br><\/h2>\n\n\n\n<h3 class=\"wp-block-heading has-heading-5-font-size\" id=\"h-in-an-iga-nephropathy-mouse-model-the-protective-effects-of-sparsentan-were-assessed-against-vehicle-on-engineered-immune-complexes-eic-induced-glomerular-proliferation-and-gene-dysregulation-in-the-kidney-1\"><span class=\"fw-600\">In an IgA nephropathy mouse model, the protective effects of sparsentan were assessed against vehicle on engineered immune complexes (EIC)-induced glomerular proliferation and gene dysregulation in the kidney<sup>1<\/sup><\/span><\/h3>\n\n\n\n<div style=\"height:15px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<h4 class=\"wp-block-heading has-heading-5-font-size\" id=\"h-background\"><br><span class=\"fw-600\"><mark style=\"background-color:rgba(0, 0, 0, 0)\" class=\"has-inline-color has-ocean-blue-color\">Background<\/mark><\/span><\/h4>\n\n\n\n<div style=\"height:12px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p>IgA nephropathy is the most common primary glomerulonephritis worldwide and a leading cause of kidney failure.<sup>2<\/sup> Up to 40% of patients develop kidney failure within 20 years of diagnosis resulting in a reduced life expectancy.<sup>1<\/sup> There is a need for new therapies to treat IgA nephropathy.<sup>1<\/sup><\/p>\n\n\n\n<div style=\"height:20px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p>Sparsentan is a non-immunosuppressive, single-molecule, Dual Endothelin Angiotensin Receptor Antagonist (DEARA).<sup>3<\/sup><\/p>\n\n\n\n<div style=\"height:20px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p>While the nephroprotection potential of sparsentan has been demonstrated in the <span style=\"text-decoration: underline;\"><a href=\"https:\/\/clleancode.top\/travere-redesign\/publications\/efficacy-and-safety-of-sparsentan-versus-irbesartan-in-patients-with-iga-nephropathy-protect-2-year-results-from-a-randomised-active-controlled-phase-3-trial-2\/\">PROTECT study<\/a><\/span>, research on the mechanism of nephroprotection in IgA nephropathy is still needed.<sup>1<\/sup><\/p>\n\n\n\n<div style=\"height:20px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p>IgA nephropathy is thought to occur in a few steps<sup>4<\/sup>:<\/p>\n\n\n\n<div style=\"height:12px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n<div class=\"wp-block-list-wrapper\">\n<ol class=\"wp-block-list\">\n<li class=\"has-small-font-size\">Presence of galactose-deficient IgA1 (Gd-IgA1) is increased in circulation<\/li>\n\n\n\n<li class=\"has-small-font-size\">IgG autoantibodies recognize Gd-IgA1<\/li>\n\n\n\n<li class=\"has-small-font-size\">Immune complexes form<\/li>\n\n\n\n<li class=\"has-small-font-size\">Immune complexes are deposited in the glomeruli leading to kidney injury<\/li>\n<\/ol>\n<\/div>\n\n\n<div style=\"height:15px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<h5 class=\"wp-block-heading\" id=\"h-aim\"><br><mark style=\"background-color:rgba(0, 0, 0, 0)\" class=\"has-inline-color has-ocean-blue-color\"><span class=\"fw-600\">Aim<\/span><\/mark><\/h5>\n\n\n\n<div style=\"height:12px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p>The objective of this animal study was to assess how sparsentan affects gene expression in glomerular pathways in IgA nephropathy.<sup>1<\/sup><\/p>\n\n\n\n<div style=\"height:15px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<h5 class=\"wp-block-heading\" id=\"h-approach\"><br><mark style=\"background-color:rgba(0, 0, 0, 0)\" class=\"has-inline-color has-ocean-blue-color\"><span class=\"fw-600\">Approach<\/span><\/mark><\/h5>\n\n\n\n<div style=\"height:12px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p>Engineered immune complexes (EIC) were formed <em>in vitro<\/em> and confirmed by an immune-complex assay.<sup>1<\/sup> The formed EIC were intravenously injected into the mice.<sup>1<\/sup> The mice were divided into four groups<sup>1<\/sup>:<\/p>\n\n\n\n<div style=\"height:12px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n<div class=\"wp-block-list-wrapper\">\n<ul class=\"wp-block-list\">\n<li>Group 1 (Negative-control): Intravenous (IV) phosphate-buffered saline (PBS) and vehicle (i.e. no treatment)<\/li>\n\n\n\n<li>Group 2 (Positive control): IV EIC and vehicle<\/li>\n\n\n\n<li>Group 3: IV EIC and sparsentan 60 mg\/kg<\/li>\n\n\n\n<li>Group 4: IV EIC and sparsentan 120 mg\/kg<\/li>\n<\/ul>\n<\/div>\n\n\n<div style=\"height:20px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p>On Day 12, half of a kidney was excised from the mice.<sup>1<\/sup> RNA was extracted from the kidneys and analyzed with RNA-Seq.<sup>1<\/sup>&nbsp;<\/p>\n\n\n\n<div style=\"height:20px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p>Gene expression changes in the EIC mouse models and the effect of sparsentan in preventing or ameliorating EIC-induced profiles were evaluated at the single-gene level and at the network level.<sup>1<\/sup><\/p>\n\n\n\n<div style=\"height:15px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<h5 class=\"wp-block-heading\" id=\"h-findings\"><br><mark style=\"background-color:rgba(0, 0, 0, 0)\" class=\"has-inline-color has-ocean-blue-color\"><span class=\"fw-600\">Findings<\/span><\/mark><\/h5>\n\n\n\n<div style=\"height:12px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p><span class=\"fw-600\">In an IgA nephropathy mouse model, sparsentan protected against EIC-induced glomerular proliferation.<sup>1<\/sup><\/span><\/p>\n\n\n\n<div style=\"height:12px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p>Compared to mice who only received PBS, EIC injections increased glomerular cellularity.<sup>1<\/sup> Sparsentan prevented EIC-induced pathological changes as well as EIC-induced increase in actively proliferating mesangial cells.<sup>1<\/sup><\/p>\n\n\n\n<div style=\"height:40px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p><span class=\"fw-600\">Sparsentan also improved EIC-activated proinflammatory genes and pathways.<sup>1<\/sup><\/span><\/p>\n\n\n\n<div style=\"height:12px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p>The most significant pathways identified were<sup>1<\/sup>:<\/p>\n\n\n\n<div style=\"height:12px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n<div class=\"wp-block-list-wrapper\">\n<ul class=\"wp-block-list\">\n<li>Cytokine-mediated signaling<\/li>\n\n\n\n<li>Cellular response to type 1 interferon<\/li>\n\n\n\n<li>Type interferon signaling<\/li>\n<\/ul>\n<\/div>\n\n\n<div style=\"height:20px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p>Expression of genes in these pathways increased with EIC injections, while sparsentan decreased gene expression.<sup>1<\/sup><\/p>\n\n\n\n<div style=\"height:12px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n<div class=\"wp-block-list-wrapper\">\n<ul class=\"wp-block-list\">\n<li>Thirty-three gene modules were identified to be associated with glomerular proliferation and Ki-67-positive glomeruli (<em>P<\/em>&lt;0.05)<sup>1<\/sup><\/li>\n\n\n\n<li>The greatest gene level dysregulation was in immune and cytokine signaling functions<sup>1<\/sup><\/li>\n<\/ul>\n<\/div>\n\n\n<div style=\"height:40px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p><span class=\"fw-600\">Mice injected with EIC exhibited changes in protein kinases and transcription factors compared to mice that received EIC and sparsentan.<sup>1<\/sup><\/span><\/p>\n\n\n\n<div style=\"height:12px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p>Sparsentan-treated mice resulted in regulation of downstream hub genes that control mesangial proliferation.<sup>1<\/sup> Some of these genes were mitogen-activated protein (MAP) kinases, known to control cellular proliferation.<sup>1<\/sup><\/p>\n\n\n\n<div style=\"height:40px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p><span class=\"fw-600\">There is overlap between EIC-dysregulated and sparsentan-responsive genes in mice, and dysregulated genes often found in patients with IgA nephropathy.<sup>1<\/sup><\/span><\/p>\n\n\n\n<div style=\"height:12px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p>Most of the overlapping genes play a role in immune function and inflammation including components of the complement pathway.<sup>1<\/sup><\/p>\n\n\n\n<div style=\"height:15px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<h5 class=\"wp-block-heading\" id=\"h-key-takeaway\"><br><mark style=\"background-color:rgba(0, 0, 0, 0)\" class=\"has-inline-color has-ocean-blue-color\"><span class=\"fw-600\">Key takeaway<\/span><\/mark><\/h5>\n\n\n\n<div style=\"height:12px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<p>This IgA nephropathy mouse model demonstrated that sparsentan targets immune and inflammatory processes, which ultimately protects from mesangial hypercellularity.<sup>1<\/sup> This multi-target approach may underlie the beneficial effects of sparsentan observed in patients with IgA nephropathy.<sup>1<\/sup><br><br><br><br><br><\/p>\n\n\n\n<div class=\"newsletter\">\n\t<div class=\"newsletter-icon\">\n\t\t<span class=\"icon2-newsletter\"><\/span>\n\t<\/div>\n\t<div class=\"newsletter-text\">\n\t\t<p><strong>Sign up<\/strong> to receive scientific updates<br \/>\nfor healthcare professionals<br \/>\nfrom Travere 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\t\t\t\t\t2024\t\t\t\t<\/p>\n\t\t\t<\/div>\n\t\t\t\t\t\t\t<a href=\"https:\/\/clleancode.top\/travere-redesign\/?post_type=publication&#038;p=4939\" class=\"a-btn a-btn--secondary--blue\"  aria-label=\"Read more: Sparsentan: The First and Only Non-Immunosuppressive Therapy for the Reduction of Proteinuria in IgA Nephropathy\">\n\t\t\t\t\t<span>Read more<\/span>\n\t\t\t\t<\/a>\n\t\t\t\t\t<\/div>\n\t<\/article>\n\t\t<\/div>\n\t\t<div class=\"publication-related-btn\">\n\t\t\t<a href=\"https:\/\/clleancode.top\/travere-redesign\/publications\/\" class=\"a-btn a-btn--primary\" aria-label=\"See more\">See more<\/a>\n\t\t<\/div>\n\t<\/div>\n\n\n\n<div style=\"height:40px\" aria-hidden=\"true\" class=\"wp-block-spacer\"><\/div>\n\n\n\n<h5 class=\"wp-block-heading\" id=\"h-footnotes\" style=\"margin-bottom:calc(30px * var(--scale))\"><mark style=\"background-color:rgba(0, 0, 0, 0)\" class=\"has-inline-color has-ocean-blue-color\"><span class=\"fw-600\">Footnotes<\/span><\/mark><\/h5>\n\n\n\n<p class=\"has-small-font-size\" style=\"margin-bottom:calc(30px * var(--scale))\">DEARA, dual endothelin angiotensin receptor antagonist; EIC, engineered immune complex; Gd-IgA1, galactose-deficient IgA1; IgA, immunoglobulin A; IgG, immunoglobulin G; IV, intravenous; MAP, mitogen-activated protein; PBS, phosphate-buffered saline.<\/p>\n\n\n<div class=\"wp-block-list-wrapper\">\n<ol class=\"wp-block-list\">\n<li class=\"has-small-font-size\">Reily C et al. <em>Am J Physiol Renal Physiol<\/em>. 2024;326(5):F862-F875.<\/li>\n\n\n\n<li class=\"has-small-font-size\">Working Group of the International IgA Nephropathy Network and the Renal Pathology Society et al. <em>Kidney Int<\/em>. 2010;77:921-927.<\/li>\n\n\n\n<li class=\"has-small-font-size\">Murugesan N et al. <em>J Med Chem<\/em>. 2005;48:171-179.<\/li>\n\n\n\n<li class=\"has-small-font-size\">Placzek WJ et al. <em>PLoS One<\/em>. 2018;13(1):e0190967.<\/li>\n<\/ol>\n<\/div>\n\n\n<p class=\"has-text-align-right\" style=\"margin-top:calc(30px * var(--scale));margin-bottom:calc(300px * var(--scale))\">MA-SP-24-0085 | September 2024<\/p>\n<\/div>\n\n\t\t<\/div>\r\n\t<\/section>\r\n\t","protected":false},"featured_media":4927,"template":"","meta":{"inline_featured_image":false,"header_bg_color":"transparent","header_fixed":true,"post_description":"","post_download_link":"","journal_link":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajprenal.00253.2023","pdf_file_link":""},"product":[78],"therapeutic_area":[97],"disease_area":[174],"study_registry":[],"study_type":[189],"resource_type":[177,180],"class_list":["post-4985","publication","type-publication","status-publish","has-post-thumbnail","hentry","product-spa","therapeutic_area-neph","disease_area-igan","study_type-preclinical-animal","resource_type-publication","resource_type-summary"],"yoast_head":"<!-- This site is optimized with the Yoast SEO Premium plugin v24.9 (Yoast SEO v27.4) - https:\/\/yoast.com\/product\/yoast-seo-premium-wordpress\/ -->\n<title>Sparsentan Improves Glomerular Hypercellularity in IgAN Mouse Model | Travere Medical Affairs<\/title>\n<meta name=\"description\" content=\"Learn more about the protective effects of sparsentan demonstrated in a IgA nephropathy mouse model. 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