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WIREs Dev Biol
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Kidney: polycystic kidney disease

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Polycystic kidney disease (PKD) is a life‐threatening genetic disorder characterized by the presence of fluid‐filled cysts primarily in the kidneys. PKD can be inherited as autosomal recessive (ARPKD) or autosomal dominant (ADPKD) traits. Mutations in either the PKD1 or PKD2 genes, which encode polycystin 1 and polycystin 2, are the underlying cause of ADPKD. Progressive cyst formation and renal enlargement lead to renal insufficiency in these patients, which need to be managed by lifelong dialysis or renal transplantation. While characteristic features of PKD are abnormalities in epithelial cell proliferation, fluid secretion, extracellular matrix and differentiation, the molecular mechanisms underlying these events are not understood. Here we review the progress that has been made in defining the function of the polycystins, and how disruption of these functions may be involved in cystogenesis. WIREs Dev Biol 2014, 3:465–487. doi: 10.1002/wdev.152 This article is categorized under: Signaling Pathways > Global Signaling Mechanisms Birth Defects > Organ Anomalies
Stages of kidney development in the mouse embryo. The pronephric duct arises from the intermediate mesoderm in the mouse embryo at E9.0. The nephric duct grows caudally until it reaches the cloaca. Mesonephric tubules can be seen at E10.0. The mesonephric tubules that are found more caudally, are more developed compared to the proximal ones. Posterior cells of the intermediate mesoderm specialize to form an aggregate called metanephric mesenchyme(MM) (red). The MM gives rise to all the segments of the nephron. The ureteric bud (UB), an outgrowth from the nephric duct invades the MM by E10.5. The UB gives rise to the collecting system of the kidneys. The UB bifurcates and the induced mesenchyme, known as the cap mesenchyme (purple), surrounds the tips of the UB.
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Potential mechanisms of cystogenesis and disease progression in autosomal dominant polycystic kidney disease ADPKD.
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Models for the functions of polycystins. (a) Polycystin‐1 PC1 and Polycystin‐2 PC2 are found on the plasma membrane (PM) in this model. Activation of PC1 leads to the activation of PC2 which leads to calcium influx and changes in gene transcription. (b) Polycystins signaling through the primary cilia. Renal cilia bend in response to fluid flow. Bending of the cilia leads to the influx of calcium through polycystins. (c) and (d) Polycystins regulating G‐protein signaling. Binding of PC1 to heterotrimeric G‐proteins activates the Gα subunit and the release of the βγ subunits. This leads to the activation of adenylyl cyclases and (mitogen‐activated protein) MAP kinases that can affect several cellular processes such as cell proliferation, fluid secretion, and differentiation. G‐protein signaling through polycystins can also affect the c‐Jun N‐terminal kinase (JNK)/activator protein‐1 (AP‐1) and nuclear factor of activated T‐cells (NFAT)/AP‐1 pathways. (e) Polycystins signaling through the JAK‐STAT signaling pathway. (e) Membrane‐anchored PC1 binds to JAK2 and activates it which then phosphorylates STAT3. (f) PC1 cytoplasmic tail can translocate to the nucleus and coactivate STAT1, 3, and 6 which were already activated independently through cytokine signaling. Once in the nucleus, STAT transcription factors affect the expression of genes required for cell proliferation, cell growth, differentiation, and apoptosis. (g) Polycystins regulating the JAK‐STAT signaling pathway. PC1, in a reaction requiring PC2, activates JAK2 that leads to the phosphorylation of STAT1. Phosphorylated STAT1 translocates to the nucleus and activates the cyclin‐dependent kinase inhibitor, p21. Activation of p21 results in the subsequent inhibition of cdk2 and cell cycle arrest.
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Structure of polycystins. Polycystin‐1 (PC1) has a large extracellular domain, 11 transmembrane domain and a short C tail. The coiled‐coil domain in the C‐terminal end of PC1 interacts with the C‐terminal tail of Polycystin‐2 (PC2). PC2 has cytoplasmic N‐ and C‐terminus. Together, PC1 and PC2 mediate calcium entry into cells. (Reprinted with permission from Ref . Copyright 2002, American Society of Nephrology)
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Stages of nephrogenesis. The adult metanephric kidney in mammals develops by a reciprocal interaction between the epithelial ureteric bud (UB) (blue) and the metanephric mesenchyme (MM) (purple). During the condensation stage, the loose mesenchymal cells of the MM condense around the tips of the epithelial UB. After the condensation stage, the induced mesenchyme undergoes a mesenchyme‐to‐epithelial conversion forms the comma and S‐shaped structures. Later, the tubules elongate and the podocytes in the glomeruli fold to give rise to a mature nephron.
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