Synbindin Downregulation Participates in Slit Diaphragm Dysfunction

Abstract

<b><i>Introduction:</i></b> Synbindin, originally identified as a neuronal cytoplasmic molecule, was found in glomeruli. The cDNA subtractive hybridization technique showed the mRNA expression of synbindin in glomeruli was downregulated in puromycin aminonucleoside (PAN) nephropathy, a mimic of minimal-change nephrotic syndrome. <b><i>Methods:</i></b> The expression of synbindin in podocytes was analyzed in normal rats and 2 types of rat nephrotic models, anti-nephrin antibody-induced nephropathy, a pure slit diaphragm injury model, and PAN nephropathy, by immunohistochemical analysis and RT-PCR techniques. To elucidate the function of synbindin, a gene silencing study with human cultured podocytes was performed. <b><i>Results:</i></b> Synbindin was mainly expressed at the slit diaphragm area of glomerular epithelial cells (podocytes). In both nephrotic models, decreased mRNA expression and the altered staining of synbindin were already detected at the early phase when proteinuria and the altered staining of nephrin, a key molecule of slit diaphragm, were not detected yet. Synbindin staining was clearly reduced when severe proteinuria was observed. When the cultured podocytes were treated with siRNA for synbindin, the cell changed to a round shape, and filamentous actin structure was clearly altered. The expression of ephrin-B1, a transmembrane protein at slit diaphragm, was clearly lowered, and synaptic vesicle-associated protein 2B (SV2B) was upregulated in the synbindin knockdown cells. <b><i>Conclusion:</i></b> Synbindin participates in maintaining foot processes and slit diaphragm as a downstream molecule of SV2B-mediated vesicle transport. Synbindin downregulation participates in slit diaphragm dysfunction. Synbindin can be an early marker to detect podocyte injury.

Lycopene from tomatoes and tomato products exerts renoprotective effects by ameliorating oxidative stress, apoptosis, pyroptosis, fibrosis, and inflammatory injury in calcium oxalate nephrolithiasis: the underlying mechanisms

“…[19][20][21]46 Ivanov et al recently demonstrated that Trappc4 is an early marker for detecting podocyte injury and participates in slit diaphragm dysfunction in puromycin aminonucleoside nephropathy. 18 However, only a few studies have investigated the regulatory role of Trappc4 in nephrolithiasis. In this study, Trappc4 protein expression was lower in the crystal group than in the control group.…”

“…Previous studies have revealed that Trappc4, one of the five candidate proteins, regulates cellular apoptosis and is involved in kidney injury. 18,20,21 In addition, Trappc4 strongly interacted with lycopene (binding energy is −6.9 kcal mol −1 ), indicating that lycopene maintains a strong stable binding state with Trappc4. Therefore, Trappc4 should be investigated further in future studies.…”

“…Trafficking protein particle subunit 4 (Trappc4), also known as synbindin, is a core subunit of the Trapp complex 16 involved in vesicle-mediated trafficking, which is required for protein targeting and secretion. 17 Several studies have revealed that Trappc4 plays a role in kidney injury 18 and regulates cell proliferation and apoptosis in various diseases. [19][20][21] Trappc4 mediates the extracellular signal-regulated kinase1/2 (ERK1/2) signaling pathway in gastric and colorectal cancers, [20][21][22][23] which is pivotal for cell proliferation and apoptosis.…”