BBA - Molecular Basis of Disease (v.1812, #10)

Autosomal dominant polycystic kidney disease: Genetics, mutations and microRNAs by Ying-Cai Tan; Jon Blumenfeld; Hanna Rennert (1202-1212).
Autosomal dominant polycystic kidney disease (ADPKD) is a common, monogenic multi-systemic disorder characterized by the development of renal cysts and various extrarenal manifestations. Worldwide, it is a common cause of end-stage renal disease. ADPKD is caused by mutation in either one of two principal genes, PKD1 and PKD2, but has large phenotypic variability among affected individuals, attributable to PKD genic and allelic variability and, possibly, modifier gene effects. Recent studies have generated considerable information regarding the genetic basis and molecular diagnosis of this disease, its pathogenesis, and potential strategies for targeted treatment. The purpose of this article is to provide a comprehensive review of the genetics of ADPKD, including mechanisms responsible for disease development, the role of gene variations and mutations in disease presentation, and the putative role of microRNAs in ADPKD etiology. The emerging and important role of genetic testing and the advent of novel molecular diagnostic applications also are reviewed. This article is part of a Special Issue entitled: Polycystic Kidney Disease.► Autosomal dominant polycystic kidney disease caused by PKD1 or PKD2 mutations. ► Phenotypic variability mainly attributed to PKD genic and allelic variability. ► Multiple genetic mechanisms including microRNAs can affect cytogenesis and disease. ► Genetic testing is available and increasingly useful for ADPKD patient management. ► Strong databases and computational tools greatly aid with ADPKD mutation Analysis.
Keywords: ADPKD; PKD gene; Mutation; Gene variation; Polycystic kidney disease; Variants of uncertain significance;

The roles of epigenetic modulation of gene expression and protein functions in autosomal dominant polycystic kidney disease (ADPKD) have recently become the focus of scientific investigation. Evidence generated to date indicates that one of the epigenetic modifiers, histone deacetylases (HDACs), are important regulators of ADPKD. HDACs are involved in regulating the expression of the Pkd1 gene and are the target of fluid flow-induced calcium signal in kidney epithelial cells. Pharmacological inhibition of HDAC activity has been found to reduce the progression of cyst formation and slow the decline of kidney function in Pkd1 conditional knockout mice and Pkd2 knockout mice, respectively, implicating the potential clinical application of HDAC inhibitors on ADPKD. Since the expression of HDAC6 is upregulated in cystic epithelial cells, the potential roles of HDAC6 in regulating cilia resorption and epidermal growth factor receptor (EGFR) trafficking through deacetylating α-tubulin and regulating Wnt signaling through deacetylating β-catenin are also discussed. This article is part of a Special Issue entitled: Polycystic Kidney Disease.► HDACs regulate the expression of Pkd1 gene. ► HDAC5 is the target of fluid-flow induced calcium signal. ► HDAC inhibition prevents cyst formation in kidney.
Keywords: Epigenetic; Autosomal dominant polycystic kidney disease; Histone deacetylases; HDAC inhibitor; α-Tubulin; Epidermal growth factor receptor;

Phosphorylation, protein kinases and ADPKD by Xiaohong Li (1219-1224).
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by renal cyst formation and caused by mutations in the PKD1 and PKD2 genes, which encode polycystin-1(PC-1) and -2 (PC-2) proteins, respectively. PC-1 is a large plasma membrane receptor involved in the regulation of several biological functions and signaling pathways including the Wnt cascade, AP-1, PI3kinase/Akt, GSK3β, STAT6, Calcineurin/NFAT and the ERK and mTOR cascades. PC-2 is a calcium channel of the TRP family. The two proteins form a functional complex and prevent cyst formation, but the precise mechanism(s) involved remains unknown. This article is part of a Special Issue entitled: Polycystic Kidney Disease.► Growing evidence suggests a role for polycystin-1 in phosphorylation and cell signaling. ► Polycystin-1 regulates several signaling cascades including Wnt, AP-1, PI3kinase/Akt, GSK3β, STAT6, the ERK and mTOR cascades. ► cAMP excess is involved in the pathogenesis of ADPKD. ► Protein kinase X can restore normal function to PKD1-deficient kidneys.
Keywords: Polycystic kidney disease; PRKX; cAMP-dependent protein kinase; Phosphorylation; Polycystin-1; Polycystin-2;

Receptor protein tyrosine phosphatases are novel components of a polycystin complex by Catherine A. Boucher; Heather H. Ward; Ruth L. Case; Katie S. Thurston; Xiaohong Li; Andrew Needham; Elsa Romero; Deborah Hyink; Seema Qamar; Tamara Roitbak; Samantha Powell; Christopher Ward; Patricia D. Wilson; Angela Wandinger-Ness; Richard N. Sandford (1225-1238).
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutation of PKD1 and PKD2 that encode polycystin-1 and polycystin-2. Polycystin-1 is tyrosine phosphorylated and modulates multiple signaling pathways including AP-1, and the identity of the phosphatases regulating polycystin-1 are previously uncharacterized. Here we identify members of the LAR protein tyrosine phosphatase (RPTP) superfamily as members of the polycystin-1complex mediated through extra- and intracellular interactions. The first extracellular PKD1 domain of polycystin-1 interacts with the first Ig domain of RPTPσ, while the polycystin-1 C-terminus of polycystin-1 interacts with the regulatory D2 phosphatase domain of RPTPγ. Additional homo- and heterotypic interactions between RPTPs recruit RPTPδ. The multimeric polycystin protein complex is found localised in cilia. RPTPσ and RPTPδ are also part of a polycystin-1/E-cadherin complex known to be important for early events in adherens junction stabilisation. The interaction between polycystin-1 and RPTPγ is disrupted in ADPKD cells, while RPTPσ and RPTPδ remain closely associated with E-cadherin, largely in an intracellular location. The polycystin-1 C-terminus is an in vitro substrate of RPTPγ, which dephosphorylates the c-Src phosphorylated Y4237 residue and activates AP1-mediated transcription. The data identify RPTPs as novel interacting partners of the polycystins both in cilia and at adhesion complexes and demonstrate RPTPγ phosphatase activity is central to the molecular mechanisms governing polycystin-dependent signaling. This article is part of a Special Issue entitled: Polycystic Kidney Disease.Diagrammatic illustration of the receptor protein tyrosine phosphatase (RPTP) type IIA subfamily and polycystin protein interactions. The cytoplasmic D1 domains of the RPTP proteins are membrane proximal and catalytic, while the D2 domains are regulatory, and serve to inactivate the phosphatase activity of the D1 domains and participate in substrate recognition. A novel interaction between RPTPγ D1 and D2 domains and the polycystins is identified and previously characterized interactions between RPTP isoforms are confirmed. The extracellular domains of the RPTPσ consist of Ig and fibronectin-like domains, which function as adhesion receptors. These domains are largely not shown except for the first Ig repeat of sigma, which serves as a ligand for the first PKD1 repeat of polycystin-1. The polycystin/RPTP protein complex can also associate with the adherens junction protein E-cadherin (not shown) and the complex can be detected at the lateral membrane and in primary cilia of normal cells. Both the complex composition and protein localisations are altered in primary ADPKD cells suggesting an important regulatory role of the RPTP in polycystin function.Display Omitted► The PKD domain of polycystin-1 interacts with receptor protein tyrosine phosphatases. ► The polycystin-RPTP complex is localised to the primary cilium. ► RPTPs regulate tyrosine phosphorylation of the C-terminus of polycystin-1. ► Tyrosine phosphorylation of polycystin-1 regulates AP-1 signalling.
Keywords: Polycystins; Tyrosine kinase; Tyrosine phosphatase; Adherens junctions; Primary cilium; G-protein coupled signaling;

Epithelial cell polarity is essential for the establishment and maintenance of morphological and functional asymmetries that underlie normal renal structure and function and are brought about by the appropriate delivery of growth factor receptors and ion and fluid transporters and channels to apical or basolateral cell membranes. The fundamental process of cellular polarization is established early during development and is controlled by sets of evolutionarily conserved proteins that integrate intrinsic and extrinsic polarity cues. Specialized structural domains between adjacent cells and cells with their matrix, termed adherens junctions (AJ) and focal adhesions (FA), respectively, are formed that contain specific components of multi-molecular complexes acting as sites to recruit proteins and to activate intracellular mechano-transduction pathways. Regulation of these processes results in tight spatio-temporal control of renal tubule growth and lumen diameter. Abnormalities in macromolecular polarization complexes lead to a variety of diseases in different organs, a common example of which is Polycystic Kidney Disease (PKD), where epithelial cysts replace normal renal tubules. Membrane protein polarity defects in Autosomal Dominant (AD) PKD include the mis-polarization of normally basolateral membrane proteins to apical, lumenal membranes, such as epidermal growth factor (EGFR/ErbB) receptors and Na+K+-ATPase-α1 subunit; mis-polarization of normally apical membrane proteins to basolateral membranes, including the Na+K+2Cl (NKCC1) symporter; and the failure to traffic and insert proteins into membranes resulting in their intracellular accumulation, such as E-cadherin and the β1 subunit of Na+K+-ATPase. Abnormalities in structural AJ, FA and polarity complexes in ADPKD epithelia include loss of E-cadherin, and focal adhesion kinase (FAK), MALS-3, Crb and Dlg complexes as well as disruptions in Rab/sec and syntaxin trafficking and membrane docking pathways. Since proper polarization of epithelial cells lining renal tubules is essential for normal kidney development and differentiation to prevent abnormal cystic dilation, interventions to reverse polarity defects to normal would offer therapeutic opportunities for PKD. This article is part of a Special Issue entitled: Polycystic Kidney Disease.► Apicobasal polarity of some transporters and receptors is abnormal in ADPKD ► Composition and regulation of adherens, focal adhesion and polarity complexes determine polarity ► Cystic proteins form multi-molecular complexes with adhesive polarity complexes ► Mutations in adhesive polarity complexes and trafficking proteins cause renal cyst formation
Keywords: ErbB; NaK-ATPase; Adherent junction; Focal adhesion complex; POLYCYSTIN; Lumen;

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is an inherited systemic disease with intrarenal cystogenesis as its primary characteristic. A variety of mouse models provided information on the requirement of loss of balanced polycystin levels for initiation of cyst formation, the role of proliferation in cystogenesis and the signaling pathways involved in cyst growth and expansion. Here we will review the involvement of different signaling pathways during renal development, renal epithelial regeneration and cyst formation in ADPKD, focusing on planar cell polarity (PCP) and oriented cell division (OCD). This will be discussed in context of the hypothesis that aberrant PCP signaling causes cyst formation. In addition, the role of the Hippo pathway, which was recently found to be involved in cyst growth and tissue regeneration, and well-known for regulating organ size control, will be reviewed. The fact that Hippo signaling is linked to PCP signaling makes the Hippo pathway a novel cascade in cystogenesis. The newly gained understanding of the complex signaling network involved in cystogenesis and disease progression, not only necessitates refining of the current hypothesis regarding initiation of cystogenesis, but also has implications for therapeutic intervention strategies. This article is part of a Special Issue entitled: Polycystic Kidney Disease.► Loss of OCD division is a permissive condition or an accelerating factor cyst formation. ► Hippo signaling is involved in cyst growth and is a novel cascade in cystogenesis. ► New understanding of signaling in cystogenesis shows a complex signaling network. ► The complex signaling in PKD has implications for therapeutic intervention.
Keywords: ADPKD; Polycystic kidney disease; Renal development; Renal epithelial regeneration; Planar cell polarity; Hippo signaling;

Putative roles of cilia in polycystic kidney disease by Paul Winyard; Dagan Jenkins (1256-1262).
The last 10 years has witnessed an explosion in research into roles of cilia in cystic renal disease. Cilia are membrane-enclosed finger-like projections from the cell, usually on the apical surface or facing into a lumen, duct or airway. Ten years ago, the major recognised functions related to classical “9 + 2” cilia in the respiratory and reproductive tracts, where co-ordinated beating clears secretions and assists fertilisation respectively. Primary cilia, which have a “9 + 0” arrangement lacking the central microtubules, were anatomical curiosities but several lines of evidence have implicated them in both true polycystic kidney disease and other cystic renal conditions: ranging from the homology between Caenorhabditis elegans proteins expressed on sensory cilia to mammalian polycystic kidney disease (PKD) 1 and 2 proteins, through the discovery that orpk cystic mice have structurally abnormal cilia to numerous recent studies wherein expression of nearly all cyst-associated proteins has been reported in the cilia or its basal body. Functional studies implicate primary cilia in mechanosensation, photoreception and chemosensation but it is the first of these which appears most important in polycystic kidney disease: in the simplest model, fluid flow across the apical surface of renal cells bends the cilia and induces calcium influx, and this is perturbed in polycystic kidney disease. Downstream effects include changes in cell differentiation and polarity. Pathways such as hedgehog and Wnt signalling may also be regulated by cilia. These data support important roles for cilia in the pathogenesis of cystic kidney diseases but one must not forget that the classic polycystic kidney disease proteins are expressed in several other locations where they may have equally important roles, such as in cell-cell and cell-matrix interactions, whilst it is not just aberrant cilia signalling that can lead to de-differentiation, loss of polarity and other characteristic features of polycystic kidney disease. Understanding how cilia fit into the other aspects of polycystic kidney disease biology is the challenge for the next decade. This article is part of a Special Issue entitled: Polycystic Kidney Disease.► There are broadly two types of cilia - primary/non-motile cilia and motile cilia. ► Protein products of several genes mutated in polycystic kidney disease localise to cilia & regulate a variety of processes. ► Activation of an intracellular calcium response following bending of cilia. ► Proper regulation of mTOR signalling, which is upregulated in cystic renal epithelia. ► Proper regulation of hedgehog and Wnt signalling.
Keywords: Cilia; Development; Wnt; Hedgehog; mTOR; Ciliopathy;

Cilium, centrosome and cell cycle regulation in polycystic kidney disease by Kyung Lee; Lorenzo Battini; G. Luca Gusella (1263-1271).
Polycystic kidney disease is the defining condition of a group of common life-threatening genetic disorders characterized by the bilateral formation and progressive expansion of renal cysts that lead to end stage kidney disease. Although a large body of information has been acquired in the past years about the cellular functions that characterize the cystic cells, the mechanisms triggering the cystogenic conversion are just starting to emerge. Recent findings link defects in ciliary functions, planar cell polarity pathway, and centrosome integrity in early cystic development. Many of the signals dysregulated during cystogenesis may converge on the centrosome for its central function as a structural support for cilia formation and a coordinator of protein trafficking, polarity, and cell division. Here, we will discuss the contribution of proliferation, cilium and planar cell polarity to the cystic signal and will analyze in particular the possible role that the basal bodies/centrosome may play in the cystogenetic mechanisms. This article is part of a Special Issue entitled: Polycystic Kidney Disease.► The sequence of early molecular events that trigger renal cystogenesis is unclear. ► Cell growth is required but not sufficient to trigger cystogenesis. ► Cilia and planar cell polarity defects during development lead to cystic kidneys. ► Dysregulation of polycystic proteins causes centrosome aberrations. ► Centrosome controls cilium position, cell cycle, and spindle organization.
Keywords: Cystogenesis; Kidney; Centrosome; Cell cycle; Cilium; Planar cell polarity;

Apoptosis in polycystic kidney disease by Béatrice Goilav (1272-1280).
Apoptosis is the process of programmed cell death. It is a ubiquitous, controlled process consuming cellular energy and designed to avoid cytokine release despite activation of local immune cells, which clear the cell fragments. The process occurs during organ development and in maintenance of homeostasis. Abnormalities in any step of the apoptotic process are associated with autoimmune diseases and malignancies. Polycystic kidney disease (PKD) is the most common inherited kidney disease leading to end-stage renal disease (ESRD). Cyst formation requires multiple mechanisms and apoptosis is considered one of them. Abnormalities in apoptotic processes have been described in various murine and rodent models of PKD as well as in human PKD kidneys. The purpose of this review is to outline the role of apoptosis in progression of PKD as well as to describe the mechanisms involved. This article is part of a Special Issue entitled: Polycystic Kidney Disease.► Apoptosis is an important factor contributing to the progression of polycystic kidney disease. ► Inhibition of apoptosis can improve renal outcome in animal models. ► Apoptosis may be an initiating factor leading to secondary proliferation.
Keywords: Polycystic kidney disease; Apoptosis; Cell Cycle; Caspases;

Calcium-mediated mechanisms of cystic expansion by Shakila Abdul-Majeed; Surya M. Nauli (1281-1290).
In this review, we will discuss several well-accepted signaling pathways toward calcium-mediated mechanisms of cystic expansion. The second messenger calcium ion has contributed to a vast diversity of signal transduction pathways. We will dissect calcium signaling as a possible mechanism that contributes to renal cyst formation. Because cytosolic calcium also regulates an array of signaling pathways, we will first discuss cilia-induced calcium fluxes, followed by Wnt signaling that has attributed to much-discussed planar cell polarity. We will then look at the relationship between cytosolic calcium and cAMP as one of the most important aspects of cyst progression. The signaling of cAMP on MAPK and mTOR will also be discussed. We infer that while cilia-induced calcium fluxes may be the initial signaling messenger for various cellular pathways, no single signaling mediator or pathway is implicated exclusively in the progression of the cystic expansion. This article is part of a Special Issue entitled: Polycystic Kidney Disease.► Primary cilia are mechanosensory organelles. ► Fluid shear stress bends and activates primary cilia. ► Activation of primary cilia promotes second messenger calcium fluxes. ► Dysfunction in primary cilia causes polycystic kidney diseases.
Keywords: Primary cilia; Mechanosensor; Signaling; Shear stress;

Cyclic AMP-mediated cyst expansion by Darren P. Wallace (1291-1300).
In polycystic kidney disease (PKD), intracellular cAMP promotes cyst enlargement by stimulating mural epithelial cell proliferation and transepithelial fluid secretion. The proliferative effect of cAMP in PKD is unique in that cAMP is anti-mitogenic in normal renal epithelial cells. This phenotypic difference in the proliferative response to cAMP appears to involve cross-talk between cAMP and Ca2+ signaling to B-Raf, a kinase upstream of the MEK/ERK pathway. In normal cells, B-Raf is repressed by Akt (protein kinase B), a Ca2+-dependent kinase, preventing cAMP activation of ERK and cell proliferation. In PKD cells, disruption of intracellular Ca2+ homeostasis due to mutations in the PKD genes relieves Akt inhibition of B-Raf, allowing cAMP stimulation of B-Raf, ERK and cell proliferation. Fluid secretion by cystic cells is driven by cAMP-dependent transepithelial Cl secretion involving apical cystic fibrosis transmembrane conductance regulator (CFTR) Cl channels. This review summarizes the current knowledge of cAMP-dependent cyst expansion, focusing on cell proliferation and Cl-dependent fluid secretion, and discusses potential therapeutic approaches to inhibit renal cAMP production and its downstream effects on cyst enlargement. This article is part of a Special Issue entitled: Polycystic Kidney Disease.► cAMP stimulates the proliferation of PKD cystic epithelial cells, but not normal renal cells, through activation of the ERK mitogen-activated protein kinase pathway. ► Aberrant intracellular calcium signaling and/or reduced steady-state calcium levels in PKD cells determine the mitogenic response to cAMP. ► cAMP stimulates solute and fluid secretion through activation of CFTR-dependent chloride secretion. ► Several approaches to reduce renal cAMP and inhibit cAMP-dependent cell proliferation and fluid secretion are being considered for the treatment of PKD.
Keywords: Polycystic kidney disease; cAMP; Calcium; Cell proliferation; MAP kinase; Fluid secretion;

Epidermal growth factor-mediated proliferation and sodium transport in normal and PKD epithelial cells by Nadezhda N. Zheleznova; Patricia D. Wilson; Alexander Staruschenko (1301-1313).
Members of the epidermal growth factor (EGF) family bind to ErbB (EGFR) family receptors which play an important role in the regulation of various fundamental cell processes including cell proliferation and differentiation. The normal rodent kidney has been shown to express at least three members of the ErbB receptor family and is a major site of EGF ligand synthesis. Polycystic kidney disease (PKD) is a group of diseases caused by mutations in single genes and is characterized by enlarged kidneys due to the formation of multiple cysts in both kidneys. Tubule cells proliferate, causing segmental dilation, in association with the abnormal deposition of several proteins. One of the first abnormalities described in cell biological studies of PKD pathogenesis was the abnormal mislocalization of the EGFR in cyst lining epithelial cells. The kidney collecting duct (CD) is predominantly an absorptive epithelium where electrogenic Na+ entry is mediated by the epithelial Na+ channel (ENaC). ENaC-mediated sodium absorption represents an important ion transport pathway in the CD that might be involved in the development of PKD. A role for EGF in the regulation of ENaC-mediated sodium absorption has been proposed. However, several investigations have reported contradictory results indicating opposite effects of EGF and its related factors on ENaC activity and sodium transport. Recent advances in understanding how proteins in the EGF family regulate the proliferation and sodium transport in normal and PKD epithelial cells are discussed here. This article is part of a Special Issue entitled: Polycystic Kidney Disease.► ErbB receptors and its ligands involved in renal development, physiology and pathophysiology.. ► ErbB activation and mislocalization are important in the progression of PKD. ► EGF and its related growth factors have a biphasic effect on ENaC-mediated sodium absorption. ► ENaC-mediated sodium absorption might be involved in the development of PKD.
Keywords: Polycystic kidney disease; ADPKD; ARPKD; ENaC; Epidermal growth factor; ErbB receptor; ErbB2;

Fluid transport and cystogenesis in autosomal dominant polycystic kidney disease by Sara Terryn; Anh Ho; Renaud Beauwens; Olivier Devuyst (1314-1321).
Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited nephropathy. The development and enlargement of cysts in ADPKD requires tubular cell proliferation, abnormalities in the extracellular matrix and transepithelial fluid secretion. Multiple studies have suggested that fluid secretion across ADPKD cyst-lining cells is driven by the transepithelial secretion of chloride, mediated by the apical CFTR channel and specific basolateral transporters. The whole secretory process is stimulated by increased levels of cAMP in the cells, probably reflecting modifications in the intracellular calcium homeostasis and abnormal stimulation of the vasopressin V2 receptor. This review will focus on the pathophysiology of fluid secretion in ADPKD cysts, starting with classic, morphological and physiological studies that were followed by investigations of the molecular mechanisms involved and therapeutic trials targeting these pathways in cellular and animal models and ADPKD patients. This article is part of a Special Issue entitled: Polycystic Kidney Disease.►Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited nephropathy. The development and enlargement of cysts in ADPKD requires tubular cell proliferation, abnormalities in the extracellular matrix and transepithelial fluid secretion. ►Fluid secretion across ADPKD cyst-lining cells is driven by the transepithelial secretion of chloride, mediated by specific channels and transporters expressed in the apical and basolateral membrane domains. ►The whole secretory process is stimulated by increased levels of cAMP in the cells, probably reflecting modifications in the intracellular calcium homeostasis and abnormal stimulation of the vasopressin V2 receptor. ►We review the pathophysiology of fluid secretion in ADPKD cysts, including morphological and physiological studies, investigations of the molecular mechanisms involved, and therapeutic trials targeting these pathways in cellular and animal models and ADPKD patients.
Keywords: Chloride; CFTR; NKCC1; Aquaporins; Vasopressin; Osmoregulation; Epithelial cell; Polycystins; Na+-K+-ATPase;

Polycystic kidney disease is the most common heritable disease in humans. In addition to epithelial cysts in the kidney, liver and pancreas, patients with autosomal dominant polycystic kidney disease (ADPKD) also suffer from abdominal hernia, intracranial aneurysm, gastrointestinal cysts, and cardiac valvular defects, conditions often associated with altered extracellular matrix production or integrity. Despite more than a decade of work on the principal ADPKD genes, PKD1 and PKD2, questions remain about the basis of cystic disease and the role of extracellular matrix in ADPKD pathology. This review explores the links between polycystins, focal adhesions, and extracellular matrix gene expression. These relationships suggest roles for polycystins in cell–matrix mechanosensory signaling that control matrix production and morphogenesis. This article is part of a Special Issue entitled: Polycystic Kidney Disease.►Changes in extracellular matrix composition and cell–matrix interactions have long been associated with ADPKD but remain understudied and poorly understood. ►Further examination of cell–matrix interaction will contribute to our understanding of cystogenesis as well as help clarify the basis of extrarenal manifestations of ADPKD that include abdominal hernia, intracranial aneurysm, gastrointestinal cysts, and cardiac valvular defects, conditions that are commonly associated with altered extracellular matrix integrity. ►In addition to their proposed role in primary cilia, polycystins might play a direct role in extracellular matrix sensing or metabolism by acting as mechanosensors in focal adhesion complexes.
Keywords: Polycystin; Focal adhesion; Mechanosensory; Extracellular matrix; Autosomal dominant; Polycystic kidney disease;

The age on onset of decline in renal function and end-stage renal disease (ESRD) in autosomal polycystic kidney disease (ADPKD) is highly variable and there are currently no prognostic tools to identify patients who will progress rapidly to ESRD. In ADPKD, expansion of cysts and loss of renal function are associated with progressive fibrosis. Similar to the correlation between tubulointerstitial fibrosis and progression of chronic kidney disease (CKD), in ADPKD, fibrosis has been identified as the most significant manifestation associated with an increased rate of progression to ESRD. Fibrosis in CKD has been studied extensively. In contrast, little is known about the mechanisms underlying progressive scarring in ADPKD although some commonality may be anticipated. Current data suggest that fibrosis associated with ADPKD shares at least some of the “classical” features of fibrosis in CKD (increased interstitial collagens, changes in matrix metalloproteinases (MMPs), over-expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), over-expression of plasminogen activator inhibitor-1 (PAI-1) and increased transforming growth factor beta (TGFβ) but that there are also some unique and stage-specific features. Epithelial changes appear to precede and to drive interstitial changes leading to the proposal that development of fibrosis in ADPKD is biphasic with alterations in cystic epithelia precipitating changes in interstitial fibroblasts and that reciprocal interactions between these cell types drives progressive accumulation of extracellular matrix (ECM). Since fibrosis is a major component of ADPKD it follows that preventing or slowing fibrosis should retard disease progression with obvious therapeutic benefits. The development of effective anti-fibrotic strategies in ADPKD is dependent on understanding the precise mechanisms underlying initiation and progression of fibrosis in ADPKD and the role of the intrinsic genetic defect in these processes. This article is part of a Special Issue entitled: Polycystic Kidney Disease.► In ADPKD, expansion of cysts is accompanied by progressive fibrosis leading to end-stage renal failure. ► In CKD of diverse etiologies, tubulointerstitial fibrosis provides the best correlation with progression to organ failure and has been studied extensively. ► Similar to CKD, fibrosis in ADPKD is associated with a more rapid decline in renal function. ► Although fibrosis in ADPKD shares some features of CKD fibrosis there are unique, stage-specific features. ► Anti-fibrotic therapies may prove an effective adjunct to treatment of ADPKD.
Keywords: Fibroblasts; Myofibroblasts; Fibrosis; Extracellular matrix; Epithelial–fibroblast interactions; Chronic kidney disease;

Polycystic kidney disease: Pathogenesis and potential therapies by Vinita Takiar; Michael J. Caplan (1337-1343).
Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent, inherited condition for which there is currently no effective specific clinical therapy. The disease is characterized by the progressive development of fluid-filled cysts derived from renal tubular epithelial cells which gradually compress the parenchyma and compromise renal function. Current interests in the field focus on understanding and exploiting signaling mechanisms underlying disease pathogenesis as well as delineating the role of the primary cilium in cystogenesis. This review highlights the pathogenetic pathways underlying renal cyst formation as well as novel therapeutic targets for the treatment of PKD. This article is part of a Special Issue entitled: Polycystic Kidney Disease.► Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common genetic disorder. ► ADPKD causes cystic enlargement of the kidneys, and often results in renal failure. ► Mutations in the genes encoding polycystin-1 and polycystin-2 cause ADPKD. ► The polycystin-1 and 2 proteins are partially localized to the primary cilium. ► The polycystin-1 and 2 proteins participate in a large number of signaling pathways.
Keywords: Polycystic kidney disease; Cilium; Proliferation; Signaling;

Adult human CD133/1+ kidney cells isolated from papilla integrate into developing kidney tubules by Heather H. Ward; Elsa Romero; Angela Welford; Gavin Pickett; Robert Bacallao; Vincent H. Gattone; Scott A. Ness; Angela Wandinger-Ness; Tamara Roitbak (1344-1357).
Approximately 60,000 patients in the United States are waiting for a kidney transplant due to genetic, immunologic and environmentally caused kidney failure. Adult human renal stem cells could offer opportunities for autologous transplant and repair of damaged organs. Current data suggest that there are multiple progenitor types in the kidney with distinct localizations. In the present study, we characterize cells derived from human kidney papilla and show their capacity for tubulogenesis. In situ, nestin+ and CD133/1+ cells were found extensively intercalated between tubular epithelia in the loops of Henle of renal papilla, but not of the cortex. Populations of primary cells from the renal cortex and renal papilla were isolated by enzymatic digestion from human kidneys unsuited for transplant and immuno-enriched for CD133/1+ cells. Isolated CD133/1+ papillary cells were positive for nestin, as well as several human embryonic stem cell markers (SSEA4, Nanog, SOX2, and OCT4/POU5F1) and could be triggered to adopt tubular epithelial and neuronal-like phenotypes. Isolated papillary cells exhibited morphologic plasticity upon modulation of culture conditions and inhibition of asymmetric cell division. Labeled papillary cells readily associated with cortical tubular epithelia in co-culture and 3-dimensional collagen gel cultures. Heterologous organ culture demonstrated that CD133/1+ progenitors from the papilla and cortex became integrated into developing kidney tubules. Tubular epithelia did not participate in tubulogenesis. Human renal papilla harbor cells with the hallmarks of adult kidney stem/progenitor cells that can be amplified and phenotypically modulated in culture while retaining the capacity to form new kidney tubules. This article is part of a Special Issue entitled: Polycystic Kidney Disease.Human CD133/1+ and nestin+ cells intercalated in tubules deep within the kidney papilla exhibit morphologic plasticity and the capacity to undergo tubulogenesis in vitro. (1) Lectin-stained, developing kidney tubules in metanephric organ culture. (2) CD133/1+ and nestin+ cells intercalated in Tamm–Horsfall labeled loops of Henle. (3) CD133/1+ cells form spheroids in culture. (4) Cortical Tamm–Horsfall labeled loops of Henle are devoid of dually CD133/1+ and nestin+ cells. (5) Isolated CD133/1+ papillary cell stained for actin and nestin.Display Omitted►Human CD133/1+ and nestin+ cells are intercalated in loop of Henle tubules deep within the kidney papilla. ►Isolated CD133/1+ and nestin+ cells express embryonic stem cell marker SSEA4 and exhibit morphologic plasticity in vitro. ►Human renal progenitors undergo tubulogenesis in metanephric organ culture. ►Heterologous metanephric organ culture can be used to identify and characterize adult human stem cells.
Keywords: Kidney disease; ADPKD; Regenerative medicine; Renopoietic; Mesenchymal stem cell; Tamm–Horsfall/uromodulin; Metanephric organ culture; Xanthosine;