"Idiopathic" Minimal Change nephrotic syndrome: A podocyte mystery nears the end.

The discovery of Zinc Fingers and Homeoboxes (ZHX) transcriptional factors and upregulation of hypo-sialylated Angiopoietin-like 4 (ANGPTL4) in podocytes have been crucial in explaining the cardinal manifestations of human Minimal Change Nephrotic Syndrome (MCNS). 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 towards alternative binding partners like IL-4Rα. During disease relapse, high plasma soluble IL-4Rα (sIL-4Rα) associated with chronic atopy complements the cytokine milieu of a common cold to displace ZHX1 from podocyte transmembrane IL-4Rα toward the podocyte nucleus. Nuclear ZHX1 induces severe upregulation of ANGPTL4 , resulting in incomplete sialylation of part of the ANGPTL4 protein, secretion of hypo-sialylated ANGPTL4 and hypo-sialylation related injury in the glomerulus. This pattern of injury induces many of the classic manifestations of human 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 hypo-sialylation injury to improve the clinical phenotype. Improving sialylation of podocyte secreted ANGPTL4 also reduces proteinuria and improves experimental MCD. Neutralizing circulating TNF-α, IL-6 or sIL-4Rα 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.