Schip1 Is a Novel Podocyte Foot Process Protein that Mediates Actin Cytoskeleton Rearrangements and Forms a Complex with Nherf2 and Ezrin

Abstract

BackgroundPodocyte foot process effacement accompanied by actin cytoskeleton rearrangements is a cardinal feature of many progressive human proteinuric diseases.ResultsBy microarray profiling of mouse glomerulus, SCHIP1 emerged as one of the most highly enriched transcripts. We detected Schip1 protein in the kidney glomerulus, specifically in podocytes foot processes. Functionally, Schip1 inactivation in zebrafish by morpholino knock-down results in foot process disorganization and podocyte loss leading to proteinuria. In cultured podocytes Schip1 localizes to cortical actin-rich regions of lamellipodia, where it forms a complex with Nherf2 and ezrin, proteins known to participate in actin remodeling stimulated by PDGFβ signaling. Mechanistically, overexpression of Schip1 in vitro causes accumulation of cortical F-actin with dissolution of transversal stress fibers and promotes cell migration in response to PDGF-BB stimulation. Upon actin disassembly by latrunculin A treatment, Schip1 remains associated with the residual F-actin-containing structures, suggesting a functional connection with actin cytoskeleton possibly via its interaction partners. A similar assay with cytochalasin D points to stabilization of cortical actin cytoskeleton in Schip1 overexpressing cells by attenuation of actin depolymerisation.ConclusionsSchip1 is a novel glomerular protein predominantly expressed in podocytes, necessary for the zebrafish pronephros development and function. Schip1 associates with the cortical actin cytoskeleton network and modulates its dynamics in response to PDGF signaling via interaction with the Nherf2/ezrin complex. Its implication in proteinuric diseases remains to be further investigated.

Cyclosporine A protects podocytes by regulating WAVE1 phosphorylation

“…Proteinuria is one of the most common manifestations of kidney disease, and it is a major risk factor for the progression of kidney disease to end-stage renal failure 1 . In recent years, many reports have shown that altered podocyte actin cytoskeletal structure is a common event that leads to podocyte foot process (FP) effacement and proteinuria 2 3 4 5 6 7 8 . It is now widely accepted that the podocyte is a direct target of many classic antiproteinuric drugs.…”

A novel assay to assess the effect of pharmaceutical compounds on the differentiation of podocytes

“…Except for Arhgap24, which strongly decreased, several cytoskeletal proteins were only mildly affected. Notably, the expression of the recently described podocyte‐specific actin cytoskeleton‐associated protein Schip1 (Perisic et al, ) increased by 76 ± 5% already after 3 days. The amount of podocyte‐specific matrix and cell matrix proteins remained stable or even slightly increased.…”

“…In cell culture, it was shown that Schip1 is localized at lamellipodia together with F‐actin, Nherf2 and ezrin. Interestingly, it was found by several groups that Schip1 is a PDGF‐B response gene inducing migration after stimulation with PDGF‐B (Chen et al, ; Schmahl et al, ; Perisic et al, ). Rac1, another migration‐regulating protein, was up‐regulated in culture throughout.…”

Homozygous nonsense mutation in SCHIP1/IQCJ‐SCHIP1 causes a neurodevelopmental brain malformation syndrome

“…11 A Schip1 role in kidney development was suggested in a microarray screen for glomerular expression in mice, 12 and by its localization to podocyte foot processes in kidney glomeruli. 13…”