Abstract
The irreversibility of glomerulosclerotic changes depends on the degree of podocyte injury. We have previously demonstrated the endocytic translocation of podocin to the subcellular area in severely injured podocytes and found that this process is the primary disease trigger. Here we identified the protein sorting nexin 9 (SNX9) as a novel facilitator of podocin endocytosis in a yeast two-hybrid analysis. SNX9 is involved in clathrin-mediated endocytosis, actin rearrangement and vesicle transport regulation. Our results revealed and confirmed that SNX9 interacts with podocin exclusively through the Bin–Amphiphysin–Rvs (BAR) domain of SNX9. Immunofluorescence staining revealed the expression of SNX9 in response to podocyte adriamycin-induced injury both in vitro and in vivo. Finally, an analysis of human glomerular disease biopsy samples demonstrated strong SNX9 expression and co-localization with podocin in samples representative of severe podocyte injury, such as IgA nephropathy with poor prognosis, membranous nephropathy and focal segmental glomerulosclerosis. In conclusion, we identified SNX9 as a facilitator of podocin endocytosis in severe podocyte injury and demonstrated the expression of SNX9 in the podocytes of both nephropathy model mice and human patients with irreversible glomerular disease.
Highlights
The irreversibility of glomerulosclerotic changes depends on the degree of podocyte injury
A great deal of work has focused on clathrin-mediated endocytosis (CME), leading to an increasing understanding of the mechanisms by which the proteins involved in this process recruit cargo into developing clathrin-coated pits and subsequently form clathrin-coated vesicles[10]
We demonstrate that sorting nexin 9 (SNX9) is strongly expressed and co-localizes with podocin in both kidneys from adriamycin (ADR)-injected mice and kidney biopsy samples from human patients with glomerular diseases leading to glomerulosclerosis
Summary
The irreversibility of glomerulosclerotic changes depends on the degree of podocyte injury. An analysis of human glomerular disease biopsy samples demonstrated strong SNX9 expression and colocalization with podocin in samples representative of severe podocyte injury, such as IgA nephropathy with poor prognosis, membranous nephropathy and focal segmental glomerulosclerosis. We identified SNX9 as a facilitator of podocin endocytosis in severe podocyte injury and demonstrated the expression of SNX9 in the podocytes of both nephropathy model mice and human patients with irreversible glomerular disease. Continuous injury to the podocytes induces irreversible podocyte loss and glomerulosclerosis development, leading to chronic renal failure[2]. A great deal of work has focused on clathrin-mediated endocytosis (CME), leading to an increasing understanding of the mechanisms by which the proteins involved in this process recruit cargo into developing clathrin-coated pits and subsequently form clathrin-coated vesicles[10]. Events, an ever-expanding array of cargo has been shown to undergo endocytosis in a clathrin-independent manner[11]
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