Polycystins and mechanosensation in renal and nodal cilia

The external surfaces of the human body, as well as its internal organs, constantly experience different kinds of mechanical stimulations. For example, tubular epithelial cells of the kidney are continuously exposed to a variety of mechanical forces, such as fluid flow shear stress within the lumen of th nephron. The majority of epithelial cells along the nephron, except intercalated cells, possess a primary cilium, an organelle projecting from the cell's apical surface into the luminal space. Despite its discovery over 100 years ago, the primary cilium's function continued to elude researchers for many decades. However, recent studies indicate that renal cilia have a sensory function. Studies on polycystic kidney disease (PKD) have identified many of the molecular players, which should help solve the mystery of how the renal cilium senses fluid flow. In this review, we will summarize the recent breakthroughs in PKD research and discuss the role(s) of th polycystin signaling complex in mediating mechanosensory function by the primary cilium of renal epithelium as well as of the embryonic node. BioEssays 26:844–856, 2004. © 2004 Wiley Periodicals, Inc.

[1]  Lin Geng,et al.  Cardiac defects and renal failure in mice with targeted mutations in Pkd2 , 2000, Nature Genetics.

[2]  James P Calvet,et al.  Polycystin-1 Activation of c-Jun N-terminal Kinase and AP-1 Is Mediated by Heterotrimeric G Proteins* , 2002, The Journal of Biological Chemistry.

[3]  S. Nauli,et al.  Gating of the polycystin ion channel signaling complex in neurons and kidney cells , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  N. LaRusso,et al.  Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. , 2003, Human molecular genetics.

[5]  W. Richards,et al.  The Oak Ridge Polycystic Kidney (orpk) disease gene is required for left-right axis determination. , 2000, Development.

[6]  B. Yoder,et al.  Polaris, a protein involved in left-right axis patterning, localizes to basal bodies and cilia. , 2001, Molecular biology of the cell.

[7]  N. Murcia,et al.  Delayed cystogenesis and increased ciliogenesis associated with the re-expression of polaris in Tg737 mutant mice. , 2003, Kidney international.

[8]  B. Dworniczak,et al.  The Ion Channel Polycystin-2 Is Required for Left-Right Axis Determination in Mice , 2002, Current Biology.

[9]  S. Reeders Multilocus polycystic disease , 1992, Nature Genetics.

[10]  Y. Pei,et al.  Identification and localization of polycystin, the PKD1 gene product. , 1996, The Journal of clinical investigation.

[11]  A. Kahn,et al.  Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the β-catenin gene , 2001, Oncogene.

[12]  M. Imai,et al.  Flow-Dependent Activation of Maxi K+ Channels in Apical Membrane of Rabbit Connecting Tubule , 1998, The Journal of Membrane Biology.

[13]  W E Sweeney,et al.  Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice. , 1994, Science.

[14]  T. Takasaka,et al.  Fine structure of guinea pig vestibular kinocilium. , 1989, Acta oto-laryngologica.

[15]  W. Keane,et al.  Identification of persons at high risk for kidney disease via targeted screening: the NKF Kidney Early Evaluation Program. , 2003, Kidney international. Supplement.

[16]  L. Guay-Woodford,et al.  The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. , 2002, Journal of the American Society of Nephrology : JASN.

[17]  P. Wilson,et al.  Autocrine, endocrine and paracrine regulation of growth abnormalities in autosomal dominant polycystic kidney disease. , 1993, European journal of cell biology.

[18]  L. Ostrowski,et al.  A Proteomic Analysis of Human Cilia , 2002, Molecular & Cellular Proteomics.

[19]  A. Korngreen,et al.  Extracellular sodium regulates airway ciliary motility by inhibiting a P2X receptor , 1999, Nature.

[20]  R. Tucker,et al.  Centriole ciliation and cell cycle variability during G1 phase of BALB/c 3T3 Cells , 1989, Journal of cellular physiology.

[21]  Weining Lu,et al.  Perinatal lethality with kidney and pancreas defects in mice with a targetted Pkd1 mutation , 1997, Nature Genetics.

[22]  U. Müller,et al.  Stereocilia defects in the sensory hair cells of the inner ear in mice deficient in integrin α8β1 , 2000, Nature Genetics.

[23]  K. Spring,et al.  Removal of the MDCK Cell Primary Cilium Abolishes Flow Sensing , 2003, The Journal of Membrane Biology.

[24]  M. Sutters,et al.  Polycystin-1 transforms the cAMP growth-responsive phenotype of M-1 cells. , 2001, Kidney international.

[25]  L. Guay-Woodford,et al.  Autocrine extracellular purinergic signaling in epithelial cells derived from polycystic kidneys. , 2002, American journal of physiology. Renal physiology.

[26]  N. Heintz,et al.  To beat or not to beat: roles of cilia in development and disease. , 2003, Human molecular genetics.

[27]  C. Tabin,et al.  A two-cilia model for vertebrate left-right axis specification. , 2003, Genes & development.

[28]  G. Germino,et al.  The Molecular Basis of Focal Cyst Formation in Human Autosomal Dominant Polycystic Kidney Disease Type I , 1996, Cell.

[29]  N. Erdoğan,et al.  Prevalence of epididymal, seminal vesicle, prostate, and testicular cysts in autosomal dominant polycystic kidney disease. , 2002, Urology.

[30]  D. Wallace,et al.  Epithelial transport in polycystic kidney disease. , 1998, Physiological reviews.

[31]  P. S. St George-Hyslop,et al.  Somatic PKD2 mutations in individual kidney and liver cysts support a "two-hit" model of cystogenesis in type 2 autosomal dominant polycystic kidney disease. , 1999, Journal of the American Society of Nephrology : JASN.

[32]  M. Hediger,et al.  Polycystin-L is a calcium-regulated cation channel permeable to calcium ions , 1999, Nature.

[33]  J. Frøkiaer,et al.  Bending the Primary Cilium Opens Ca2+-sensitive Intermediate-Conductance K+ Channels in MDCK Cells , 2003, The Journal of Membrane Biology.

[34]  D. Wheatley,et al.  Cilia in cell-cultured fibroblasts. II. Incidence in mitotic and post-mitotic BHK 21-C13 fibroblasts. , 1971, Journal of anatomy.

[35]  Tanya M. Teslovich,et al.  Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome , 2003, Nature.

[36]  C. Bugg,et al.  Polaris, a protein disrupted in orpk mutant mice, is required for assembly of renal cilium. , 2002, American journal of physiology. Renal physiology.

[37]  S. Somlo,et al.  Identification of two novel polycystic kidney disease-1-like genes in human and mouse genomes. , 2003, Genomics.

[38]  Y. Saijoh,et al.  The left-right determinant Inversin is a component of node monocilia and other 9+0 cilia , 2003, Development.

[39]  G. Pazour,et al.  Chlamydomonas IFT88 and Its Mouse Homologue, Polycystic Kidney Disease Gene Tg737, Are Required for Assembly of Cilia and Flagella , 2000, The Journal of cell biology.

[40]  N. Hirokawa,et al.  Left-Right Asymmetry and Kinesin Superfamily Protein KIF3A: New Insights in Determination of Laterality and Mesoderm Induction by kif3A− /− Mice Analysis , 1999, The Journal of cell biology.

[41]  Alessandra Boletta,et al.  PKD1 Induces p21waf1 and Regulation of the Cell Cycle via Direct Activation of the JAK-STAT Signaling Pathway in a Process Requiring PKD2 , 2002, Cell.

[42]  D. Cole,et al.  Magnesium transport in the renal distal convoluted tubule. , 2001, Physiological reviews.

[43]  G. Germino,et al.  Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents , 2000, Nature.

[44]  J. Calvet,et al.  The genetics and physiology of polycystic kidney disease. , 2001, Seminars in nephrology.

[45]  T. Strachan,et al.  Expression analyses and interaction with the anaphase promoting complex protein Apc2 suggest a role for inversin in primary cilia and involvement in the cell cycle. , 2002, Human molecular genetics.

[46]  D. Hall,et al.  The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway , 2001, Current Biology.

[47]  G. Pazour,et al.  Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease , 2002, Current Biology.

[48]  R. Bacallao,et al.  Inversin forms a complex with catenins and N-cadherin in polarized epithelial cells. , 2002, Molecular biology of the cell.

[49]  T. Strachan,et al.  Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination , 2003, Nature Genetics.

[50]  M. Hommel,et al.  Significance of Early CT Signs in Acute Stroke , 2002, Cerebrovascular Diseases.

[51]  Jing Zhou,et al.  Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells , 2003, Nature Genetics.

[52]  C. Stayner,et al.  Polycystin channels and kidney disease. , 2001, Trends in pharmacological sciences.

[53]  M. Lucia,et al.  Caspases, Bcl-2 proteins and apoptosis in autosomal-dominant polycystic kidney disease. , 2002, Kidney international.

[54]  M. Hamon,et al.  Localization of 5-HT6 receptors at the plasma membrane of neuronal cilia in the rat brain , 2000, Brain Research.

[55]  M. Bronner‐Fraser,et al.  N-Cadherin, a cell adhesion molecule involved in establishment of embryonic left-right asymmetry. , 2000, Science.

[56]  L. Satlin,et al.  Epithelial Na(+) channels are regulated by flow. , 2001, American journal of physiology. Renal physiology.

[57]  J. Rosenbaum,et al.  Intraflagellar Transport: The Eyes Have It , 1999, The Journal of cell biology.

[58]  A. Woolf,et al.  OFD1, the gene mutated in oral-facial-digital syndrome type 1, is expressed in the metanephros and in human embryonic renal mesenchymal cells. , 2003, Journal of the American Society of Nephrology : JASN.

[59]  S. Schulz,et al.  Selective targeting of somatostatin receptor 3 to neuronal cilia , 1999, Neuroscience.

[60]  S. Somlo,et al.  Identification of PKD2L, a human PKD2-related gene: tissue-specific expression and mapping to chromosome 10q25. , 1998, Genomics.

[61]  L. Satlin,et al.  Ontogeny of flow-stimulated potassium secretion in rabbit cortical collecting duct: functional and molecular aspects. , 2003, American journal of physiology. Renal physiology.

[62]  T. Benzing,et al.  Interaction between RGS7 and polycystin. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[63]  S. Weremowicz,et al.  Identification and characterization of a novel polycystin family member, polycystin-L2, in mouse and human: sequence, expression, alternative splicing, and chromosomal localization. , 2000, Genomics.

[64]  U. Hopfer,et al.  Osmolar changes regulate the paracellular permeability of cultured human cervical epithelium. , 1995, The American journal of physiology.

[65]  S. Weremowicz,et al.  The sequence, expression, and chromosomal localization of a novel polycystic kidney disease 1-like gene, PKD1L1, in human. , 2002, Genomics.

[66]  P. Wilson,et al.  The autosomal recessive polycystic kidney disease protein is localized to primary cilia, with concentration in the basal body area. , 2004, Journal of the American Society of Nephrology : JASN.

[67]  Jing Zhou,et al.  Constitutive Activation of G-proteins by Polycystin-1 Is Antagonized by Polycystin-2* , 2002, The Journal of Biological Chemistry.

[68]  Jing Zhou,et al.  Molecular Complexes Formed with Polycystins , 2003, Nephron Experimental Nephrology.

[69]  B. Veldhuisen,et al.  Genes homologous to the autosomal dominant polycystic kidney disease genes (PKD1 and PKD2) , 1999, European Journal of Human Genetics.

[70]  Paul W. Sternberg,et al.  A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans , 1999, Nature.

[71]  G. Germino,et al.  Polycystin-1, the gene product of PKD1, induces resistance to apoptosis and spontaneous tubulogenesis in MDCK cells. , 2000, Molecular cell.

[72]  P. Harris,et al.  Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects. , 2001, Human molecular genetics.

[73]  Bernhard Schermer,et al.  Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis , 2003, Nature Genetics.

[74]  K. R. Spring,et al.  Bending the MDCK Cell Primary Cilium Increases Intracellular Calcium , 2001, The Journal of Membrane Biology.

[75]  N. Hirokawa,et al.  Abnormal nodal flow precedes situs inversus in iv and inv mice. , 1999, Molecular cell.

[76]  J. Hughes,et al.  The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains , 1995, Nature Genetics.

[77]  S. Weremowicz,et al.  Identification of PKDL, a Novel Polycystic Kidney Disease 2-Like Gene Whose Murine Homologue Is Deleted in Mice with Kidney and Retinal Defects* , 1998, The Journal of Biological Chemistry.

[78]  S. Weremowicz,et al.  A gene similar to PKD1 maps to chromosome 4q22: a candidate gene for PKD2. , 1996, Genomics.

[79]  K. Shiokawa,et al.  Calmodulin binds to inv protein: Implication for the regulation of inv function , 2001, Development, growth & differentiation.

[80]  Kimiko Yamamoto,et al.  Proliferation, differentiation, and tube formation by endothelial progenitor cells in response to shear stress. , 2003, Journal of applied physiology.

[81]  M. Brueckner,et al.  Two Populations of Node Monocilia Initiate Left-Right Asymmetry in the Mouse , 2003, Cell.

[82]  C. Rieder,et al.  Flexible-substratum technique for viewing cells from the side: some in vivo properties of primary (9+0) cilia in cultured kidney epithelia. , 1988, Journal of cell science.

[83]  A. Nayır,et al.  The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin , 2002, Nature Genetics.

[84]  S. Baker,et al.  The intraflagellar transport protein, IFT88, is essential for vertebrate photoreceptor assembly and maintenance , 2002, The Journal of cell biology.

[85]  Patricia A. Gabow,et al.  PKD2, a Gene for Polycystic Kidney Disease That Encodes an Integral Membrane Protein , 1996, Science.

[86]  Kenji Nakamura,et al.  Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant. , 2002, Human molecular genetics.

[87]  F. Hildebrandt,et al.  A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1 , 1997, Nature Genetics.

[88]  R. Kucherlapati,et al.  Somatic Inactivation of Pkd2 Results in Polycystic Kidney Disease , 1998, Cell.

[89]  N. Rifai,et al.  Late onset of renal and hepatic cysts in Pkd1-targeted heterozygotes , 1999, Nature Genetics.

[90]  J. Hughes,et al.  Identification of a human homologue of the sea urchin receptor for egg jelly: a polycystic kidney disease-like protein. , 1999, Human molecular genetics.

[91]  L P Sullivan,et al.  cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway. , 2000, Kidney international.