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Recently, uncovered genomic defects upstream of ZHX2 induce a ZHX2 hypomorph state that makes podocytes inherently susceptible to mild cytokine storms resulting from a common cold. In ZHX2 hypomorph podocytes, ZHX proteins are redistributed away from normal transmembrane partners like aminopeptidase A (APA) toward alternative binding partners like IL-4R\u03b1. During disease relapse, high plasma soluble IL-4R\u03b1 (sIL-4R\u03b1) associated with chronic atopy complements the cytokine milieu of a common cold to displace ZHX1 from podocyte transmembrane IL-4R\u03b1 toward the podocyte nucleus. Nuclear ZHX1 induces severe upregulation of ANGPTL4, resulting in incomplete sialylation of part of the ANGPTL4 protein, secretion of hyposialylated ANGPTL4, and hyposialylation-related injury in the glomerulus. This pattern of injury induces many of the classic manifestations of human minimal change disease (MCD), including massive and selective proteinuria, podocyte foot process effacement, and loss of glomerular basement membrane charge. Administration of glucocorticoids reduces ANGPTL4 upregulation, which reduces hyposialylation injury to improve the clinical phenotype. Improving sialylation of podocyte-secreted ANGPTL4 also reduces proteinuria and improves experimental MCD. Neutralizing circulating TNF-\u03b1, IL-6, or sIL-4R\u03b1 after the induction of the cytokine storm in Zhx2 hypomorph mice reduces albuminuria, suggesting potential new therapeutic targets for clinical trials to prevent MCD relapse. These studies collectively lay to rest prior suggestions of a role of single cytokines or soluble proteins in triggering MCD relapse. <\/jats:p>","DOI":"10.1152\/ajprenal.00219.2023","type":"journal-article","created":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T08:00:26Z","timestamp":1696492826000},"page":"F685-F694","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["\u201cIdiopathic\u201d minimal change nephrotic syndrome: a podocyte mystery nears the end"],"prefix":"10.1152","volume":"325","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1496-2804","authenticated-orcid":false,"given":"Sumant S.","family":"Chugh","sequence":"first","affiliation":[{"name":"Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lionel 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