Nephrin is involved in podocyte maturation but not survival during glomerular development

Abstract

Nephrin, a major component of the glomerular slit diaphragm (SD), is both a structural protein as well as a signaling molecule influencing foot process (FP) formation and maintenance of podocyte integrity. Analyses of near-term embryonic kidneys showed normal cellular viability and no apoptosis in glomeruli from nephrin knockout mice. Moreover, expression and location of other SD or glomerular basement membrane components were similar in wild-type and mutant mice as was the location and levels of most podocyte-specific proteins. Transcriptional profiling showed that the lack of nephrin had minor impact on the expression of genes for FPs and SD proteins. Claudin 3, a tight-junction protein normally absent in glomeruli, was upregulated threefold in the knockout mice, suggesting a role of nephrin in claudin 3 gene expression within the glomeruli. Our results suggest that nephrin is expressed late in the process of podocyte differentiation and is a locus for the formation of SD and FP maintenance and physical integrity in vivo. Nephrin does not seem to have a primary role in cell survival but has a small impact on gene regulation during glomerular development.

Pathogénie du syndrome néphrotique à lesions glomérulaires minimes

“…Nck se lie, via ses domaines SH3, à différentes protéines impliquées dans la régulation de l'actine telles que WASp et le complexe Arp2/3 [24], tandis que, via ses domaines SH2, Nck se lie aux phosphotyrosines de la Néphrine ce qui permet une connexion étroite entre la plate-forme de signalisation et l'organisation du cytosquelette d'actine. Le rôle de la phosphorylation de la Néphrine au cours de la morphogenèse podocytaire reste controversé comme en témoignent des données récentes qui montrent que les souris déficientes pour la néphrine ont un déve-loppement podocytaire normal bien que les podocytes n'expriment pas de diaphragme de fente [30]. …”

Biology of claudins

“…Both claudin-6 and TM4SF10, a closely related protein that is part of the PMP22/EMP/claudin gene superfamily, are expressed at podocyte junctions during development (15,118). Claudin-6 is also upregulated at podocyte junctions with protamine sulfate treatment and in puromycin aminogylcoside nephrosis (118), while claudin-3 is upregulated in podocytes of nephrin-knockout mice (25).…”

An update: the role of Nephrin inside and outside the kidney

“…Furthermore, KO of Nephrin in mice do not significantly affect the glomerular morphogenesis, podocyte viability or expression of other FPs and SD protein complex genes during development [19]. These data suggest that nephrin is critical for maintaining normal SD structure and prevent proteinuria.…”

“…Loss of Nephrin does not affect podocyte viability, suggesting that Nephrin can be compensated by other podocyte molecules during glomerular development [19]. Nephrin can interact with the cytoskeleton through several proteins, but the relationship between Nephrin and the other podocyte molecules has not been fully demonstrated.…”