A Novel Model for Nephrotic Syndrome Reveals Associated Dysbiosis of the Gut Microbiome and Extramedullary Hematopoiesis.
Glomerular kidney disease causing nephrotic syndrome is a complex systemic disorder and is associated with significant morbidity in affected patient populations. Despite its clinical relevance, well-established models are largely missing to further elucidate the implications of uncontrolled urinary protein loss. To overcome this limitation, we generated a novel, inducible, podocyte-specific transgenic mouse model (Epb41l5), developing nephrotic syndrome in adult mice. Animals were comprehensively characterized, including microbiome analysis and multiplexed immunofluorescence imaging. Induced knockout mice developed a phenotype consistent with focal segmental glomerular sclerosis (FSGS). Although these mice showed hallmark features of severe nephrotic syndrome (including proteinuria, hypoalbuminemia and dyslipidemia), they did not exhibit overt chronic kidney disease (CKD) phenotypes. Analysis of the gut microbiome demonstrated distinct dysbiosis and highly significant enrichment of the Alistipes genus. Moreover, Epb41l5-deficient mice developed marked organ pathologies, including extramedullary hematopoiesis of the spleen. Multiplex immunofluorescence imaging demonstrated red pulp macrophage proliferation and mTOR activation as driving factors of hematopoietic niche expansion. Thus, this novel mouse model for adult-onset nephrotic syndrome reveals the significant impact of proteinuria on extra-renal manifestations, demonstrating the versatility of this model for nephrotic syndrome-related research.
['Maier|Jasmin I|JI|0000-0003-4158-2935', 'Rogg|Manuel|M|0000-0002-6658-9159', 'Helmstädter|Martin|M|', 'Sammarco|Alena|A|', 'Walz|Gerd|G|', 'Werner|Martin|M|', 'Schell|Christoph|C|']
D000818:Animals D004195:Disease Models, Animal D064806:Dysbiosis D000069196:Gastrointestinal Microbiome D005923:Glomerulosclerosis, Focal Segmental D006411:Hematopoiesis, Extramedullary D006801:Humans D007674:Kidney Diseases D008264:Macrophages D051379:Mice D057507:Mice, 129 Strain D018345:Mice, Knockout D008822:Mice, Transgenic D008954:Models, Biological D009404:Nephrotic Syndrome D050199:Podocytes D061251:Primary Cell Culture D011506:Proteins D011507:Proteinuria
nephrotic syndrome gut microbiome extramedullary hematopoiesis EPB41L5 focal segmental glomerulosclerosis