Polycystic kidney diseases: From molecular discoveries to targeted therapeutic strategies

Abstract.Polycystic kidney diseases (PKDs) represent a large group of progressive renal disorders characterized by the development of renal cysts leading to end-stage renal disease. Enormous strides have been made in understanding the pathogenesis of PKDs and the development of new therapies. Studies of autosomal dominant and recessive polycystic kidney diseases converge on molecular mechanisms of cystogenesis, including ciliary abnormalities and intracellular calcium dysregulation, ultimately leading to increased proliferation, apoptosis and dedifferentiation. Here we review the pathobiology of PKD, highlighting recent progress in elucidating common molecular pathways of cystogenesis. We discuss available models and challenges for therapeutic discovery as well as summarize the results from preclinical experimental treatments targeting key disease-specific pathways.

• Publication year

  2007

• Venue

  Cellular and Molecular Life Sciences

• Publication date

  2007-10-29

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1007/s00018-007-7362-xPMID 17975706PMCID 2775119
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Autosomal dominant polycystic kidney disease.

  2010cited by this paper
• Vasopressin antagonists in polycystic kidney disease.

  2008cited by this paper
• Polycystic kidney disease: genes, proteins, animal models, disease mechanisms and therapeutic opportunities

  2007cited by this paper
• Fibrocystin/Polyductin, Found in the Same Protein Complex with Polycystin-2, Regulates Calcium Responses in Kidney Epithelia

  2007cited by this paper
• Characterization of cis-Autoproteolysis of Polycystin-1, the Product of Human Polycystic Kidney Disease 1 Gene*

  2007cited by this paper
• Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.

  2007cited by this paper
• Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome.

  2007cited by this paper
• Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway.

  2007cited by this paper
• The intraflagellar transport component IFT88/polaris is a centrosomal protein regulating G1-S transition in non-ciliated cells

  2007cited by this paper
• The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome

  2007cited by this paper
• Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease

  2007cited by this paper
• The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.

  2007cited by this paper
• Polyductin undergoes notch-like processing and regulated release from primary cilia.

  2007cited by this paper
• Autosomal dominant polycystic kidney disease: time for a change?

  2007cited by this paper
• Volume progression in polycystic kidney disease.

  2006cited by this paper
• Cilia: tuning in to the cell's antenna.

  2006cited by this paper
• Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine

  2006cited by this paper
• A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days

  2006cited by this paper
• Proteolytic Cleavage and Nuclear Translocation of Fibrocystin Is Regulated by Intracellular Ca2+ and Activation of Protein Kinase C*

  2006cited by this paper
• Development of polycystic kidney disease in juvenile cystic kidney mice: insights into pathogenesis, ciliary abnormalities, and common features with human disease.

  2006cited by this paper
• Volume progression in polycystic kidney disease.

  2006cited by this paper
• The Primary Cilium as the Cell's Antenna: Signaling at a Sensory Organelle

  2006cited by this paper
• Increased water intake decreases progression of polycystic kidney disease in the PCK rat.

  2006cited by this paper
• Overexpression of PKD1 Causes Polycystic Kidney Disease

  2006cited by this paper
• Therapeutic approaches in autosomal dominant polycystic kidney disease (ADPKD): is there light at the end of the tunnel?

  2006cited by this paper
• The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease.

  2006cited by this paper
• Early embryonic renal tubules of wild-type and polycystic kidney disease kidneys respond to cAMP stimulation with cystic fibrosis transmembrane conductance regulator/Na(+),K(+),2Cl(-) Co-transporter-dependent cystic dilation.

  2006cited by this paper
• Renal failure causes early death of bcl-2 deficient mice.

  2006cited by this paper
• In vitro cystogenesis: the search for drugs antagonizing cyst development.

  2006cited by this paper
• Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease.

  2006cited by this paper
• Polycystin-1 and polycystin-2 regulate the cell cycle through the helix–loop–helix inhibitor Id2

  2005cited by this paper
• Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease.

  2005cited by this paper
• Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease?

  2005cited by this paper
• Roscovitine Targets, Protein Kinases and Pyridoxal Kinase*[boxs]

  2005cited by this paper
• Cystic Renal Neoplasia Following Conditional Inactivation of Apc in Mouse Renal Tubular Epithelium*

  2005cited by this paper
• Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways

  2005cited by this paper
• Vasopressin antagonists in polycystic kidney disease.

  2005cited by this paper
• Impaired formation of desmosomal junctions in ADPKD epithelia

  2005cited by this paper
• Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD).

  2005cited by this paper
• Cilium-generated signaling and cilia-related disorders

  2005cited by this paper
• Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease.

  2005cited by this paper
• Differential expression of E-cadherin, N-cadherin and beta-catenin in proximal and distal segments of the rat nephron.

  2004cited by this paper
• Epidermal growth factor receptor tyrosine kinase inhibition is not protective in PCK rats.

  2004cited by this paper
• Polyductin, the PKHD1 gene product, comprises isoforms expressed in plasma membrane, primary cilium, and cytoplasm.

  2004cited by this paper
• Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus.

  2004cited by this paper
• Heart rate variability and short duration spaceflight: relationship to post-flight orthostatic intolerance

  2004cited by this paper
• Calcium Restriction Allows cAMP Activation of the B-Raf/ERK Pathway, Switching Cells to a cAMP-dependent Growth-stimulated Phenotype*

  2004cited by this paper
• The relationship between cell proliferation, Cl- secretion, and renal cyst growth: a study using CFTR inhibitors.

  2004cited by this paper
• Autosomal recessive polycystic kidney disease

  2004cited by this paper
• The N-terminal Extracellular Domain Is Required for Polycystin-1-dependent Channel Activity*

  2004cited by this paper
• Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease.

  2004cited by this paper
• PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD)

  2004cited by this paper
• Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease.

  2004cited by this paper
• Polycystic kidney disease: new understanding in the pathogenesis.

  2004cited by this paper
• A functional floxed allele of Pkd1 that can be conditionally inactivated in vivo.

  2004cited by this paper
• Murine models of polycystic kidney disease: molecular and therapeutic insights.

  2003cited by this paper
• β4 Integrin and Laminin 5 Are Aberrantly Expressed in Polycystic Kidney Disease : Role in Increased Cell Adhesion and Migration

  2003cited by this paper
• A complete mutation screen of PKHD1 in autosomal-recessive polycystic kidney disease (ARPKD) pedigrees.

  2003cited by this paper
• Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells

  2003cited by this paper
• Functional analysis of PKD1 transgenic lines reveals a direct role for polycystin-1 in mediating cell-cell adhesion.

  2003cited by this paper
• Terminal Renal Failure in Mice Lacking Transcription Factor AP-2β

  2003cited by this paper
• Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease

  2003cited by this paper
• A polycystin-1 multiprotein complex is disrupted in polycystic kidney disease cells.

  2003cited by this paper
• Autosomal dominant polycystic kidney disease.

  2003cited by this paper
• EGF receptor tyrosine kinase inhibition attenuates the development of PKD in Han:SPRD rats.

  2003cited by this paper
• Beta4 integrin and laminin 5 are aberrantly expressed in polycystic kidney disease: role in increased cell adhesion and migration.

  2003cited by this paper
• Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype.

  2003cited by this paper
• Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia.

  2003cited by this paper
• Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys.

  2003cited by this paper
• Polycystin-2 is an intracellular calcium release channel

  2002cited by this paper
• PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats.

  2002cited by this paper
• Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease.

  2002cited by this paper
• Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations

  2002cited by this paper
• The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein

  2002cited by this paper
• Cell Cycle via Direct Activation of the JAK-STAT Signaling Pathway in a Process Requiring PKD2

  2002cited by this paper
• Functional polycystin-1 expression is developmentally regulated during epithelial morphogenesis in vitro: downregulation and loss of membrane localization during cystogenesis.

  2002cited by this paper
• Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel

  2001cited by this paper
• Tuberin-dependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene.

  2001cited by this paper
• Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel.

  2001cited by this paper
• Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the β-catenin gene

  2001cited by this paper
• Bending the MDCK Cell Primary Cilium Increases Intracellular Calcium

  2001cited by this paper
• Chlamydomonas IFT88 and Its Mouse Homologue, Polycystic Kidney Disease Gene Tg737, Are Required for Assembly of Cilia and Flagella

  2000cited by this paper
• Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents

  2000cited by this paper
• Polycystin Expression in the Kidney and Other Tissues: Complexity, Consensus and Controversy

  2000cited by this paper
• Polycystin 1 is required for the structural integrity of blood vessels.

  2000cited by this paper
• Loss of heterozygosity in renal and hepatic epithelial cystic cells from ADPKD1 patients

  2000cited by this paper
• Strong homophilic interactions of the Ig-like domains of polycystin-1, the protein product of an autosomal dominant polycystic kidney disease gene, PKD1.

  2000cited by this paper
• Polycystin-1, the product of the polycystic kidney disease 1 gene, co-localizes with desmosomes in MDCK cells.

  2000cited by this paper
• Genetic evidence for a trans-heterozygous model for cystogenesis in autosomal dominant polycystic kidney disease.

  2000cited by this paper
• A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype.

  2000cited by this paper
• Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor.

  2000cited by this paper
• The PKD1 gene product, "polycystin-1," is a tyrosine-phosphorylated protein that colocalizes with alpha2beta1-integrin in focal clusters in adherent renal epithelia.

  1999cited by this paper
• Polycystin-1, the PKD1 gene product, is in a complex containing E-cadherin and the catenins.

  1999cited by this paper
• Somatic PKD2 mutations in individual kidney and liver cysts support a "two-hit" model of cystogenesis in type 2 autosomal dominant polycystic kidney disease.

  1999cited by this paper
• Bcl-2 overexpression prevents apoptosis-induced Madin-Darby canine kidney simple epithelial cyst formation.

  1999cited by this paper
• The Polycystic Kidney Disease 1 Gene Product Modulates Wnt Signaling*

  1999cited by this paper
• A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans

  1999cited by this paper
• Apoptosis in cystogenesis: hands on or hands off?

  1999cited by this paper
• Epithelial transport in polycystic kidney disease.

  1998cited by this paper
• Chloride and fluid secretion in polycystic kidney disease.

  1998cited by this paper

• Macrophage Accumulation and Cyst Expansion in Pkd2, Ift88, and Double Mutant Mouse Models.

  2025cites this paper
• HNF1β bookmarking involves Topoisomerase 1 activation and DNA topology relaxation in mitotic chromatin.

  2024cites this paper
• Functions of the primary cilium in the kidney and its connection with renal diseases.

  2023cites this paper
• Calcium signaling in polycystic kidney disease- cell death and survival.

  2023cites this paper
• Semaphorin-3C Is Upregulated in Polycystic Kidney Epithelial Cells and Inhibits Angiogenesis of Glomerular Endothelial Cells

  2020cites this paper
• Autosomal dominant polycystic kidney disease: Disrupted pathways and potential therapeutic interventions

  2019influential citation
• Polycystin‐1 affects cancer cell behaviour and interacts with mTOR and Jak signalling pathways in cancer cell lines

  2019cites this paper
• Autosomal Dominant Polycystic Kidney Disease and Genetic Counseling

  2019cites this paper
• Role of PKR in the Inhibition of Proliferation and Translation by Polycystin-1

  2019cites this paper
• Impact of miR‐192 and miR‐194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease

  2018cites this paper
• On the Many Actions of Ouabain: Pro-Cystogenic Effects in Autosomal Dominant Polycystic Kidney Disease

  2017cites this paper
• Profiling conserved biological pathways in Autosomal Dominant Polycystic Kidney Disorder (ADPKD) to elucidate key transcriptomic alterations regulating cystogenesis: A cross-species meta-analysis approach.

  2017cites this paper
• Functional analysis of Bicc1 and novel interacting proteins in renal tubule cell metabolism and polycystic kidneys

  2017cites this paper
• Polycystic Kidney Disease: ADPKD and ARPKD

  2016cites this paper
• Human mutations affect the epigenetic/bookmarking function of HNF1B

  2016cites this paper
• Ouabain Enhances ADPKD Cell Apoptosis via the Intrinsic Pathway

  2016cites this paper
• AVANÇOS NO TRATAMENTO DA DOENÇA RENAL POLIQUÍSTICA AUTOSSÓMICA DOMINANTE

  2015cites this paper
• Epigenetic silencing of the MUPCDH gene as a possible prognostic biomarker for cyst growth in ADPKD

  2015cites this paper
• The Regulation of a Pathogenic Macrophage Polarization by IL-10 in Polycystic Kidney Disease

  2015cites this paper
• THE ROLE OF MACROPHAGES IN THE PROGRESSION OF POLYCYSTIC KIDNEY DISEASE

  2014cites this paper
• SVEUČILIŠTE U ZAGREBU MEDICINSKI FAKULTET

  2014influential citation
• The exocyst and regulatory GTPases in urinary exosomes

  2014cites this paper
• Genome-wide methylation profiling of ADPKD identified epigenetically regulated genes associated with renal cyst development

  2014cites this paper
• Kidney: polycystic kidney disease

  2014cites this paper
• Mouse models of polycystic kidney disease induced by defects of ciliary proteins

  2013cites this paper
• The Ciliary Protein Cystin Forms a Regulatory Complex with Necdin to Modulate Myc Expression

  2013cites this paper
• microRNA biomarkers in cystic diseases

  2013cites this paper
• Analysis of the REJ Module of Polycystin-1 Using Molecular Modeling and Force-Spectroscopy Techniques

  2013cites this paper
• N‐myc downstream‐regulated gene 1 is involved in the regulation of cystogenesis in transgenic mice overexpressing human PKD2 gene

  2013cites this paper
• Role of microRNAs in kidney homeostasis and disease.

  2012cites this paper
• The Discovery of Samsca® (Tolvaptan): The First Oral Nonpeptide Vasopressin Receptor Antagonist

  2012cites this paper
• Benign Renal Tumors

  2012cites this paper
• collecting duct cells enlargement and cyst formation by cultured mammalian cAMP-dependent chloride secretion mediates tubule

  2012cites this paper
• The fate of bone marrow-derived cells carrying a polycystic kidney disease mutation in the genetically normal kidney

  2012influential citation
• The role of the cilium in normal and abnormal cell cycles: emphasis on renal cystic pathologies

  2012cites this paper
• Polycystins and Autosomal Polycystic Kidney Disease

  2012cites this paper
• Transforming growth factor-β inhibits cystogenesis in human autosomal dominant polycystic kidney epithelial cells.

  2012cites this paper
• Regulation of cell proliferation in autosomal dominant polycystic kidney disease

  2011influential citation
• Planar cell polarity in kidney development and disease

  2011cites this paper
• Ectopic expression of cadherin 8 is sufficient to cause cyst formation in a novel 3D collagen matrix renal tubule culture.

  2011cites this paper
• Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease

  2011cites this paper
• Genetics of an Ovine PKD Model

  2011cites this paper
• Polycystic kidney disease: inheritance, pathophysiology, prognosis, and treatment

  2010cites this paper
• Genetics of Fibrocystic Diseases of the Liver and Molecular Approaches to Therapy

  2010cites this paper
• Naturally Occurring Osmolytes Modulate the Nanomechanical Properties of Polycystic Kidney Disease Domains*

  2010cites this paper
• Riboregulators in kidney development and function.

  2010cites this paper
• Polycystic liver diseases.

  2010cites this paper
• Colchicine treatment in autosomal dominant polycystic kidney disease: many points in common.

  2010cites this paper
• A metabolomics approach using juvenile cystic mice to identify urinary biomarkers and altered pathways in polycystic kidney disease.

  2010cites this paper
• Pathology of Fibrocystic Diseases of the Liver

  2010cites this paper
• cAMP-dependent chloride secretion mediates tubule enlargement and cyst formation by cultured mammalian collecting duct cells.

  2009cites this paper
• The primary cilium as a cellular signaling center: lessons from disease.

  2009cites this paper
• Activation of the AKT/mTOR pathway in autosomal recessive polycystic kidney disease (ARPKD).

  2009cites this paper
• A role for microRNA in cystic liver and kidney diseases.

  2008cites this paper
• Serum and urinary biomarker signatures for rapid preclinical in vivo assessment of CDK inhibition as a therapeutic approach for PKD

  2008cites this paper
• Modeling ciliopathies: Primary cilia in development and disease.

  2008cites this paper
• Chapter 5 Modeling Ciliopathies

  2008cites this paper
• International Journal of Nephrology and Renovascular Disease Dovepress

  year unknowncites this paper