Abstract
Podocytes are a major component of the glomerular blood filtration barrier, and alterations to the morphology of their unique actin-based foot processes (FP) are a common feature of kidney disease. Adjacent FP are connected by a specialized intercellular junction known as the slit diaphragm (SD), which serves as the ultimate barrier to regulate passage of macromolecules from the blood. While the link between SD dysfunction and reduced filtration selectivity has been recognized for nearly 50 years, our understanding of the underlying molecular circuitry began only 20 years ago, sparked by the identification of NPHS1, encoding the transmembrane protein nephrin. Nephrin not only functions as the core component of the extracellular SD filtration network but also as a signaling scaffold via interactions at its short intracellular region. Phospho-regulation of several conserved tyrosine residues in this region influences signal transduction pathways which control podocyte cell adhesion, shape, and survival, and emerging studies highlight roles for nephrin phospho-dynamics in mechanotransduction and endocytosis. The following review aims to summarize the last 5 years of advancement in our knowledge of how signaling centered at nephrin directs SD barrier formation and function. We further provide insight on promising frontiers in podocyte biology, which have implications for SD signaling in the healthy and diseased kidney.
Highlights
Nephrin acts as the core of the SD and as a signaling hub in the podocyte, modulating cell polarity, survival, adhesion, cytoskeletal organization, mechanosensing, and SD turnover
The frontier is to mobilize the insight gained from over two decades of “nephr(in)ology” research into novel therapies that target this unique indispensable protein and the molecules it communicates with
Summary
The nephron is the blood filtering subunit of the kidney and each is made up of a glomerulus, the site of primary filtration, as well as a network of tubules where this filtrate is concentrated and further refined before it passes to the bladder to await excretion [2]. The glomerular basement membrane (GBM), a compilation of proteins produced by podocytes and endothelial cells [4], lies at the interface of the two cell types. These three layers collectively constitute the GFB [5]. The podocyte’s anionic glycocalyx, composed mainly of podocalyxin [8], provides additional charge-dependent resistance against the passage of negatively charged proteins Together, their contribution toward both the size and charge basis for selective filtration positions podocytes as the key component of the GFB, and they are a primary target of injury in kidney disease [1, 2]
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