Moderate Nucleoporin 133 deficiency leads to glomerular damage in zebrafish

Abstract

Although structural nuclear pore proteins (nucleoporins) are seemingly required in every cell type to assemble a functional nuclear transport machinery, mutations or deregulation of a subset of them have been associated with specific human hereditary diseases. In particular, previous genetic studies of patients with nephrotic syndrome identified mutations in Nup107 that impaired the expression or the localization of its direct partner at nuclear pores, Nup133. In the present study, we characterized the zebrafish nup133 orthologous gene and its expression pattern during larval development. Using a morpholino-mediated gene knockdown, we show that partial depletion of Nup133 in zebrafish larvae leads to the formation of kidney cysts, a phenotype that can be rescued by co-injection of wild type mRNA. Analysis of different markers for tubular and glomerular development shows that the overall kidney development is not affected by nup133 knockdown. Likewise, no gross defect in nuclear pore complex assembly was observed in these nup133 morphants. On the other hand, nup133 downregulation results in proteinuria and moderate foot process effacement, mimicking some of the abnormalities typically featured by patients with nephrotic syndrome. These data indicate that nup133 is a new gene required for proper glomerular structure and function in zebrafish.

From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

“…Morphant zebrafish with nup107 knock-down [87] as well as CRISPR/Cas9mediated in-frame mutations in nup107 [90] mimicked the allelic effects seen in human patients and caused hypoplastic glomerulus structures and pathological podocyte foot processes. Morpholino-mediated depletion of nup133 in zebrafish likewise led to the formation of kidney cysts, moderate foot process effacement and proteinuria, while the overall kidney development was not impaired [95]. Consistent with the results in zebrafish models, morpholino-mediated knock-down of nup107, nup85, or nup133 in Xenopus caused defects in glomerular structure and function [90].…”

15-keto-Prostaglandin E2 exhibits bioactive role by modulating glomerular cytoarchitecture through EP2/EP4 receptors

“…4). In addition to the labeled podocytes and parietal epithelial cells in these transgenics, we performed the angiography using bovine serum albumin (BSA) conjugated with AlexaFluor555 to mark the endothelial cells of glomerular capillaries as previously described [59]. We visualized glomeruli development and its vascularization throughout five different stages; at 30, 48, 52, 72, 120 hpf.…”

Nuclear pore complexes in development and tissue homeostasis

“…Studies on Nup133 and Nup107, both members of the same scaffold subcomplex, have provided some insights into the role of Nups in kidney physiology. Spatiotemporal analysis of Nup133 expression during zebrafish development has shown that, by 5 days post-fertilization, this Nup is mainly expressed in liver, but also in pronephric proximal tubules and the glomerulus at lower levels (Cianciolo Cosentino et al, 2019). Morpholinomediated knockdown of Nup133 results in glomerular expansion, formation of kidney cysts, and liver misplacement.…”