Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States.
Am J Physiol Renal Physiol. 2023 Dec 1;325(6):F685-F694. doi: 10.1152/ajprenal.00219.2023. Epub 2023 Oct 5.
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 induce a hypomorph state that makes podocytes inherently susceptible to mild cytokine storms resulting from a common cold. In 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 , 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 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 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.
锌指和同源盒（ZHX）转录因子的发现以及足细胞中低唾液酸化的血管生成素样 4（ANGPTL4）的上调，对于解释人类微小病变肾病综合征（MCNS）的主要表现至关重要。最近，在 上游发现的基因组缺陷导致了一个 低功能状态，使足细胞对普通感冒引起的轻度细胞因子风暴天生敏感。在 低功能的足细胞中，ZHX 蛋白从正常的跨膜伴侣（如氨肽酶 A（APA））重新分布到替代的结合伴侣，如 IL-4Rα。在疾病复发期间，与慢性特应性皮炎相关的高血浆可溶性 IL-4Rα（sIL-4Rα）补充了普通感冒的细胞因子环境，将 ZHX1 从足细胞跨膜 IL-4Rα 置换到足细胞核内。核内的 ZHX1 诱导严重的 上调，导致部分 ANGPTL4 蛋白的不完全唾液酸化、低唾液酸化的 ANGPTL4 分泌以及肾小球中的低唾液酸化相关损伤。这种损伤模式引发了人类微小病变病（MCD）的许多典型表现，包括大量和选择性蛋白尿、足细胞足突消失以及肾小球基底膜电荷丧失。糖皮质激素的给药可降低 的上调，从而减少低唾液酸化损伤，改善临床表型。改善足细胞分泌的 ANGPTL4 的唾液酸化也可减少蛋白尿并改善实验性 MCD。在 低功能小鼠的细胞因子风暴诱导后，中和循环中的 TNF-α、IL-6 或 sIL-4Rα 可减少白蛋白尿，提示潜在的新治疗靶点，用于临床试验以预防 MCD 复发。这些研究共同消除了先前关于单一细胞因子或可溶性蛋白在触发 MCD 复发中的作用的建议。
