Glcci1 Deficiency Leads to Proteinuria

Abstract

Unbiased transcriptome profiling and functional genomics approaches identified glucocorticoid-induced transcript 1 (GLCCI1) as being a transcript highly specific for the glomerulus, but its role in glomerular development and disease is unknown. Here, we report that mouse glomeruli express far greater amounts of Glcci1 protein compared with the rest of the kidney. RT-PCR and Western blotting demonstrated that mouse glomerular Glcci1 is approximately 60 kD and localizes to the cytoplasm of podocytes in mature glomeruli. In the fetal kidney, intense Glcci1 expression occurs at the capillary-loop stage of glomerular development. Using gene knockdown in zebrafish with morpholinos, morphants lacking Glcci1 function had collapsed glomeruli with foot-process effacement. Permeability studies of the glomerular filtration barrier in these zebrafish morphants demonstrated a disruption of the selective glomerular permeability filter. Taken together, these data suggest that Glcci1 promotes the normal development and maintenance of podocyte structure and function.

The struggle for energy in podocytes leads to nephrotic syndrome

“…90 One of the highly glomerulus-specific transcripts identified encodes glucocorticoid-induced transcript 1 (glcci1, ENSMUSG00000029638), which is expressed at 14-fold higher rates in the glomerulus than in the rest of the kidney. 90,91 Glcci1 is highly expressed in mouse glomerular podocytes, and its mRNA and protein levels were upregulated by dexamethasone. 91 The biochemical function of glcci1, including its ligand, is completely unknown.…”

“…90,91 Glcci1 is highly expressed in mouse glomerular podocytes, and its mRNA and protein levels were upregulated by dexamethasone. 91 The biochemical function of glcci1, including its ligand, is completely unknown. However, based on its amino acid sequence, which shows > 60 serine/ threonine phosphorylation sites in the approximately 60-kDa protein, glcci1 may be a powerful substrate for a large number of signaling kinases and may thereby interfere with their activation by depriving them of energy.…”

A Photo Shoot of Proteinuria

“…17 Therefore, several investigators have successfully used the fish model system to show that deletion of genes in podocytes resulted in podocyte dysfunction and deficiency of the size-selective kidney barrier. [17][18][19][20][21][22][23][24] Over the past several years, zebrafish have emerged as an ideal model to study vertebrate development. The transparency of the zebrafish embryos allows direct visualization of tissue morphogenesis such as glomerular development as it occurs in a live organism.…”

“…These assays seem to be both fairly costintensive, especially when considering large-scale screens, and largely dependent on assay techniques. 23 Using a fluorescent marker of proteinuria overcomes most of these limitations, which may be interesting in the future. From the perspective of a nephrologist, screening for novel drugs that prevent podocyte death and the development of progressive glomerulosclerosis would be most desirable.…”

Fishing for New Glomerular Disease-Related Genes

“…In the current issue of JASN, Nishibori et al report on another one of the more than 300 genes originally identified by this group. 7 Glucocorticoid-induced transcript 1, GLCCI1, is expressed in the glomerulus of the mouse kidney at an elevated level, according to their GlomBase and GlomChip data. 8 In the current article, this group confirms the original data, first with an in vitro analysis, followed by immunohistochemistry.…”