"Idiopathic" minimal change nephrotic syndrome: a podocyte mystery nears the end

Abstract

The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated 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 (APA) toward 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 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-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.

Keywords: atopy; cytokine storm; minimal change disease; nephrotic syndrome; podocyte.

Graphical abstract

Figure 1.

Schematic representation of minimal change disease (MCD) relapse induced by a common cold cytokine storm in the setting of chronic atopy and a Zhx2 hypomorph state. Top: cytokine cocktail components, relevant cytokine receptors in podocytes, endothelial and mesangial cells, and the contribution of sIL-4Rα by chronic atopy. IL-4Rα forms two receptor complexes, IL-4R1 and IL-4R2, in podocytes. Bottom: normal zinc fingers and homeoboxes (ZHX) protein heterodimer distribution in in vivo podocytes (left), altered ZHX protein heterodimer and homodimer distribution in the Zhx2 hypomorph state (middle), and dual Zhx2 hypomorph and Enpep-deficient states (right). The normal transmembrane binding partner for ZHX3-ZHX2 at the slit diaphragm is ephrin B1 and for ZHX1-ZHX2 in the podocyte body is aminopeptidase A (APA). In a Zhx2-deficient state, ZHX1 homodimers and possibly ZHX1-ZHX2 heterodimers also bind to the cytoplasmic tail of IL-4Rα. In a dual Zhx2 hypomorph-Enpep-deficient state, a larger amount of ZHX1 homodimers and ZHX1-ZHX2 heterodimers likely bind IL-4Rα. ZHX-mediated MCD relapse pathways start from the podocyte body, whereas ZHX-mediated focal and segmental glomerulosclerosis (FSGS) relapses originate from the slit diaphragm and foot processes. Endo, endothelium; ICAM-1, intercellular adhesion molecule-1; sICAM-1, soluble ICAM-1; TNFR1, tumor necrosis ractor receptor type 1; IL-2R γ, interleukin 2 receptor subunit γ; IL-4R α, interleukin 4 receptor subunit α; IL-13R α1, interleukin 13 receptor subunit α1; sIL-4R α, soluble IL-4R α; WT1, Wilms’ tumor 1; IL-10R α, interleukin 10 receptor subunit α; IL-10R β, interleukin 10 receptor subunit β; IL-6ST, interleukin 6 cytokine family signal transducer.

Figure 2.

Flowsheet showing consequences of podocyte angiopoietin-like 4 (ANGPTL4) upregulation and the pathogenesis of “hyposialylation injury” in minimal change disease (MCD). GBM, glomerular basement membrane.