Research priorities for autosomal dominant polycystic kidney disease: a UK priority setting partnership.

Objectives: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney condition, accounting for 7%-10% of patients with kidney failure. Fundamental basic science and clinical research on ADPKD is underway worldwide but no one has yet considered which areas should be prioritised to maximise returns from limited future funding. The Polycystic Kidney Disease Charity began a priority setting partnership with the James Lind Alliance (JLA) in the UK in 2019-2020 to identify areas of uncertainty in the ADPKD care pathway and allow patients, carers and healthcare professionals to rank the 10 most important questions for research.

Urinary exosome proteomic profiling defines stage-specific rapid progression of autosomal dominant polycystic kidney disease and tolvaptan efficacy.

ADPKD is the most common genetic disease of the kidney leading to end-stage renal disease necessitating renal replacement therapy at any time between the 1 and 8 decades of life due to widely variable rates of disease progression. This presents significant patient anxiety and a significant prognostic and therapeutic challenge. Tolvaptan is the only approved drug licensed to slow ADPKD progression by reducing renal cystic expansion but side-effects can limit its efficacy.

Collecting duct cells show differential retinoic acid responses to acute versus chronic kidney injury stimuli.

Retinoic acid (RA) activates RA receptors (RAR), resulting in RA response element (RARE)-dependent gene expression in renal collecting duct (CD). Emerging evidence supports a protective role for this activity in acute kidney injury (AKI) and chronic kidney disease (CKD). Herein, we examined this activity in RARE-LacZ transgenic mice and by RARE-Luciferase reporter assays in CD cells, and investigated how this activity responds to neurotransmitters and mediators of kidney injury.

Novel biomarkers in kidney disease: roles for cilia, Wnt signalling and ATMIN in polycystic kidney disease.

Biomarkers, the measurable indicators of biological conditions, are fast becoming a popular approach in providing information to track disease processes that could lead to novel therapeutic interventions for chronic conditions. Inherited, chronic kidney disease affects millions of people worldwide and although pharmacological treatments exist for some conditions, there are still patients whose only option is kidney dialysis and kidney transplantation. In the past 10 years, certain chronic kidney diseases have been reclassified as ciliopathies.

Therapeutic targets for polycystic kidney disease.

Introduction: Polycystic kidney disease (PKD) is a common genetic disease in which renal enlargement and loss of function is caused by progressive expansion of tubular cysts. To reverse the detrimental effects of PKD gene mutation(s) and to slow cystic expansion, new drug therapies are required.

Areas Covered: The underlying cell biology leading to identification of molecular targets for PKD is reviewed.

Urine microRNA as potential biomarkers of autosomal dominant polycystic kidney disease progression: description of miRNA profiles at baseline.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is clinically heterogenic. Biomarkers are needed to predict prognosis and guide management. We aimed to profile microRNA (miRNA) in ADPKD to gain molecular insight and evaluate biomarker potential.

Retinoic acid receptor-dependent, cell-autonomous, endogenous retinoic acid signaling and its target genes in mouse collecting duct cells.

Background: Vitamin A is necessary for kidney development and has also been linked to regulation of solute and water homeostasis and to protection against kidney stone disease, infection, inflammation, and scarring. Most functions of vitamin A are mediated by its main active form, all-trans retinoic acid (tRA), which binds retinoic acid receptors (RARs) to modulate gene expression. We and others have recently reported that renal tRA/RAR activity is confined to the ureteric bud (UB) and collecting duct (CD) cell lineage, suggesting that endogenous tRA/RARs primarily act through regulating gene expression in these cells in embryonic and adult kidney, respectively.

PRKX critically regulates endothelial cell proliferation, migration, and vascular-like structure formation.

Angiogenesis is a fundamental step in several important physiological events and pathological conditions including embryonic development, wound repair, tumor growth and metastasis. PRKX was identified as a novel type-I cAMP-dependent protein kinase gene expressed in multiple developing tissues. PRKX has also been shown to be phylogenetically and functionally distinct from PKA.

Apico-basal polarity in polycystic kidney disease epithelia.

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.

c-Src inactivation reduces renal epithelial cell-matrix adhesion, proliferation, and cyst formation.

c-Src is a non-receptor tyrosine kinase whose activity is induced by phosphorylation at Y418 and translocation from the cytoplasm to the cell membrane. Increased activity of c-Src has been associated with cell proliferation, matrix adhesion, motility, and apoptosis in tumors. Immunohistochemistry suggested that activated (pY(418))-Src activity is increased in cyst-lining autosomal dominant polycystic kidney disease (ADPKD) epithelial cells in human and mouse ADPKD.

Receptor protein tyrosine phosphatases are novel components of a polycystin complex.

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.

Epidermal growth factor-mediated proliferation and sodium transport in normal and PKD epithelial cells.

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.

Polycystic kidney disease protein fibrocystin localizes to the mitotic spindle and regulates spindle bipolarity.

Autosomal recessive polycystic kidney disease (ARPKD) is a significant hereditary renal disease occurring in infancy and childhood, which presents with greatly enlarged echogenic kidneys, ultimately leading to renal insufficiency and end-stage renal disease. ARPKD is caused by mutations in a single gene PKHD1, which encodes fibrocystin/polyductin (FPC), a large single transmembrane protein generally known to be on the primary cilium, basal body and plasma membrane. Here, using our newly generated antibody raised against the entire C-terminal intracellular cytoplasmic domain (ICD) of FPC, as well as our previously well-characterized antibody against a peptide of ICD, we report for the first time that at least one isoform of FPC is localized to the centrosome and mitotic spindle of dividing cells in multiple cell lines, including MDCK, mIMCD3, LLC-PK1, HEK293, RCTEC and HFCT cells.

Activator of G protein signaling 3 promotes epithelial cell proliferation in PKD.

The activation of heterotrimeric G protein signaling is a key feature in the pathophysiology of polycystic kidney diseases (PKD). In this study, we report abnormal overexpression of activator of G protein signaling 3 (AGS3), a receptor-independent regulator of heterotrimeric G proteins, in rodents and humans with both autosomal recessive and autosomal dominant PKD. Increased AGS3 expression correlated with kidney size, which is an index of severity of cystic kidney disease.

Carboxy terminal tail of polycystin-1 regulates localization of TSC2 to repress mTOR.

Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited renal disorder caused by defects in the PKD1 or PKD2 genes. ADPKD is associated with significant morbidity, and is a major underlying cause of end-stage renal failure (ESRF). Commonly, treatment options are limited to the management of hypertension, cardiovascular risk factors, dialysis, and transplantation when ESRF develops, although several new pharmacotherapies, including rapamycin, have shown early promise in animal and human studies.

EGF and its related growth factors mediate sodium transport in mpkCCDc14 cells via ErbB2 (neu/HER-2) receptor.

Amiloride-sensitive sodium entry, via the epithelial sodium channel (ENaC), is the rate-limiting step for Na(+) absorption. Epidermal growth factor (EGF) is involved in the regulation of Na(+) transport and ENaC activity. However it is still controversial exactly how EGF regulates ENaC and Na(+) absorption.

Abnormalities in focal adhesion complex formation, regulation, and function in human autosomal recessive polycystic kidney disease epithelial cells.

Integrin-associated focal adhesion complex formation and turnover plays an essential role in directing interactions between epithelial cells and the extracellular matrix during organogenesis, leading to appropriate cell spreading, cell-matrix adhesion, and migration. Autosomal recessive polycystic kidney disease (ARPKD) is associated with loss of function of PKHD1-encoded protein fibrocystin-1 and is characterized by cystic dilation of renal collecting tubules (CT) in utero and loss of renal function in patients if they survive the perinatal period. Normal polycystin-1 (PC-1)/focal adhesion complex function is required for control of CT diameter during renal development, and abnormalities in these complexes have been demonstrated in human PC-1 mutant cystic cells.

Protein kinase-X interacts with Pin-1 and Polycystin-1 during mouse kidney development.

The regulation of epithelial branching morphogenesis by bone morphogenetic protein-7 depends, in part, on functionally defined cyclic adenosine monophosphate (cAMP)-dependent protein kinases. We previously identified protein kinase-X (PRKX), a cAMP-dependent kinase, as a regulator of epithelial morphogenesis during kidney development and found that it binds to and phosphorylates Polycystin-1. Overexpression of PRKX stimulates renal epithelial cell migration, tubulogenesis, ureteric bud branching, and glomerular induction in embryonic mouse kidney explants in organ cultures.

Mouse models of polycystic kidney disease.

Polycystic kidney disease (PKD) is a diverse group of human monogenic lethal conditions inherited as autosomal dominant (AD) or recessive (AR) traits. Recent development of genetically engineered mouse models of ADPKD, ARPKD, and nephronophthisis/medullary cystic disease (NPHP) are providing additional insights into the molecular mechanisms governing of these disease processes as well as the developmental differentiation of the normal kidney. Genotypic and phenotypic mouse models are discussed and provide evidence for the fundamental involvement of cell-matrix, cell-cell, and primary cilia-lumen interactions, as well as epithelial proliferation, apoptosis, and polarization.

Pathways of apoptosis in human autosomal recessive and autosomal dominant polycystic kidney diseases.

Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end-stage renal disease in adults. Autosomal recessive (AR) PKD affects approximately 1:20,000 live-born children with high perinatal mortality. Both diseases have abnormalities in epithelial proliferation, secretion, and cell-matrix interactions, leading to progressive cystic expansion and associated interstitial fibrosis.

Mechanoregulation of intracellular Ca2+ in human autosomal recessive polycystic kidney disease cyst-lining renal epithelial cells.

Mutations of cilia-expressed proteins are associated with an attenuated shear-induced increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) in renal epithelial cell lines derived from murine models of autosomal recessive polycystic kidney disease (ARPKD). We hypothesized that human ARPKD cyst-lining renal epithelial cells also exhibited dysregulated mechanosensation. To test this, conditionally immortalized cell lines derived from human fetal ARPKD cyst-lining (pool and clone 5E) cell lines with low levels of fibrocystin/polyductin expression and age-matched normal collecting tubule [human fetal collecting tubule (HFCT) pool and clone 2C] cell lines were grown in culture, loaded with a Ca(2+) indicator dye, and subjected to laminar shear.

Cystic disease of the kidney.

This review focuses on the mechanisms that underlie the development of human renal cystic diseases. A pathological, clinical, and pathophysiological overview is given. Initial analysis of the cell biology of inappropriate hyperproliferation accompanied by fluid secretion of cyst-lining epithelia has been followed by the elucidation of fundamental defects in epithelial polarity, cell-matrix and cell-cell interactions, and apoptosis, all of which are discussed.

Protein kinase X (PRKX) can rescue the effects of polycystic kidney disease-1 gene (PKD1) deficiency.

Autosomal dominant polycystic kidney disease (ADPKD) is a common, genetically determined developmental disorder of the kidney that is characterized by cystic expansion of renal tubules and is caused by truncating mutations and haplo-insufficiency of the PKD1 gene. Several defects in cAMP-mediated proliferation and ion secretion have been detected in ADPKD cyst-lining epithelia. Unlike the ubiquitous PKA, the cAMP-dependent CREB-kinase, Protein Kinase X (PRKX) is developmentally regulated, tissue restricted and induces renal epithelial cell migration, and tubulogenesis in vitro as well as branching morphogenesis of ureteric bud in developing kidneys.

Branching morphogenesis of the ureteric epithelium during kidney development is coordinated by the opposing functions of GDNF and Sprouty1.

Branching of ureteric bud-derived epithelial tubes is a key morphogenetic process that shapes development of the kidney. Glial cell line-derived neurotrophic factor (GDNF) initiates ureteric bud formation and promotes subsequent branching morphogenesis. Exactly how GDNF coordinates branching morphogenesis is unclear.