Fluid shear modulates many biological properties. How shear mechanosensing occurs in the extracellular matrix (ECM) and is transduced into cytoskeletal change remains unknown. Cochlin is an ECM protein of unknown function. Our investigation using a comprehensive spectrum of cutting-edge techniques has resulted in following major findings: (1) over-expression and down-regulation of cochlin increase and decrease intraocular pressure (IOP), respectively. The overexpression was achieved in DBA/2J-Gpnmb+/SjJ using lentiviral vectors, down-regulation was achieved in glaucomatous DBA/2J mice using targeted disruption (cochlin-null mice) and also using lentiviral vector mediated shRNA against cochlin coding region; (2) reintroduction of cochlin in cochlin-null mice increases IOP; (3) injection of exogenous cochlin also increased IOP; (4) increasing perfusion rates increased cochlin multimerization, which reduced the rate of cochlin proteolysis by trypsin and proteinase K; The cochlin multimerization in response to shear stress suggests its potential mechanosensing. Taken together with previous studies, we show cochlin is involved in regulation of intraocular pressure in DBA/2J potentially through mechanosensing of the shear stress.
References
[1]
Kung C (2005) A possible unifying principle for mechanosensation. Nature 436: 647–654.
[2]
Robertson NG, Jones SM, Sivakumaran TA, Giersch AB, Jurado SA, et al. (2008) A targeted Coch missense mutation: a knock-in mouse model for DFNA9 late-onset hearing loss and vestibular dysfunction. Hum Mol Genet 17: 3426–3434.
[3]
Picciani R, Desai K, Guduric-Fuchs J, Cogliati T, Morton CC, et al. (2007) Cochlin in the eye: functional implications. Prog Retin Eye Res 26: 453–469.
[4]
Anderson DR (2003) Collaborative normal tension glaucoma study. Curr Opin Ophthalmol 14: 86–90.
[5]
Asrani S, Zeimer R, Wilensky J, Gieser D, Vitale S, et al. (2000) Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma 9: 134–142.
[6]
Chow J, Liton PB, Luna C, Wong F, Gonzalez P (2007) Effect of cellular senescence on the P2Y-receptor mediated calcium response in trabecular meshwork cells. Mol Vis 13: 1926–1933.
[7]
Morrison JC, Acott TS (2003) Anatomy and physiology of aqueous humor outflow. In: Morrison JC, Pollack IP, editors. Glaucoma - Science and Practice. New York: Thieme Medical Publishers Inc. pp. 34–41.
[8]
Bhattacharya SK, Rockwood EJ, Smith SD, Bonilha VL, Crabb JS, et al. (2005) Proteomics reveals cochlin deposits associated with glaucomatous trabecular meshwork. J Biol Chem 280: 6080–6084.
[9]
Patel AJ, Lazdunski M, Honore E (2001) Lipid and mechano-gated 2P domain K(+) channels. Curr Opin Cell Biol 13: 422–428.
[10]
Goel M, Sienkiewicz AE, Picciani R, Lee RK, Bhattacharya SK (2011) Cochlin Induced TREK-1 Co-Expression and Annexin A2 Secretion: Role in Trabecular Meshwork Cell Elongation and Motility. PLoS One 6: e23070.
[11]
Gabelt BT, Kaufman PL (2005) Changes in aqueous humor dynamics with age and glaucoma. Prog Retin Eye Res 24: 612–637.
[12]
John SW, Hagaman JR, MacTaggart TE, Peng L, Smithes O (1997) Intraocular pressure in inbred mouse strains. Invest Ophthalmol Vis Sci 38: 249–253.
[13]
Wang J, Wang MR, Jiang H, Shen M, Cui L, et al. (2010) Detection of magnetic particles in live DBA/2J mouse eyes using magnetomotive optical coherence tomography. Eye and Contact Lens: Science and Clinical Practice. In press.
[14]
Rodriguez CI, Cheng JG, Liu L, Stewart CL (2004) Cochlin, a secreted von Willebrand factor type a domain-containing factor, is regulated by leukemia inhibitory factor in the uterus at the time of embryo implantation. Endocrinology 145: 1410–1418.
[15]
Libby RT, Anderson MG, Pang IH, Robinson ZH, Savinova OV, et al. (2005) Inherited glaucoma in DBA/2J mice: pertinent disease features for studying the neurodegeneration. Vis Neurosci 22: 637–648.
[16]
Bhattacharya SK, Gabelt BT, Ruiz J, Picciani R, Kaufman PL (2009) Cochlin expression in anterior segment organ culture models after TGFbeta2 treatment. Invest Ophthalmol Vis Sci 50: 551–559.
[17]
Lee ES, Gabelt BT, Faralli JA, Peters DM, Brandt CR, et al. (2010) COCH transgene expression in cultured human trabecular meshwork cells and its effect on outflow facility in monkey organ cultured anterior segments. Invest Ophthalmol Vis Sci 51: 2060–2066.
[18]
Jimenez AI, Sesto A, Roman JP, Gascon I, Gonzalez de Buitrago G, Office USPaT, editor (2007) Treatment of eye disorders characterized by an elevated intraocular pressure by siRNAS. US Patent. USA: Sylentis S. A., Madrid, ES. pp. 1–22.
[19]
Heys JJ, Barocas VH, Taravella MJ (2001) Modeling passive mechanical interaction between aqueous humor and iris. J Biomech Eng 123: 540–547.
[20]
Vass CH C, Unger E, Mayr W, Georgopoulos M, Rainer G, Richter-Mueksch S (2004) Human aqueous humor viscosity in cataract, primary open angle glaucoma and pseudoexfoliation syndrome. Invest Ophthalmol Vis Sci E Abstract 45: 5030.
[21]
Sit AJ, Nau CB, McLaren JW, Johnson DH, Hodge D (2008) Circadian variation of aqueous dynamics in young healthy adults. Invest Ophthalmol Vis Sci 49: 1473–1479.
Shankaran H, Alexandridis P, Neelamegham S (2003) Aspects of hydrodynamic shear regulating shear-induced platelet activation and self-association of von Willebrand factor in suspension. Blood 101: 2637–2645.
[24]
Bhattacharya SK, Annangudi SP, Salomon RG, Kuchtey RW, Peachey NS, et al. (2005) Cochlin deposits in the trabecular meshwork of the glaucomatous DBA/2J mouse. Exp Eye Res 80: 741–744.
[25]
Vogel V (2006) Mechanotransduction involving multimodular proteins: converting force into biochemical signals. Annu Rev Biophys Biomol Struct 35: 459–488.
[26]
WuDunn D (2009) Mechanobiology of trabecular meshwork cells. Exp Eye Res 88: 718–723.
[27]
Geiger B, Bershadsky A, Pankov R, Yamada KM (2001) Transmembrane crosstalk between the extracellular matrix–cytoskeleton crosstalk. Nat Rev Mol Cell Biol 2: 793–805.
[28]
Janmey PA, Weitz DA (2004) Dealing with mechanics: mechanisms of force transduction in cells. Trends Biochem Sci 29: 364–370.
[29]
Fujiwara K (2006) Platelet endothelial cell adhesion molecule-1 and mechanotransduction in vascular endothelial cells. J Intern Med 259: 373–380.
[30]
Borras T (2003) Gene expression in the trabecular meshwork and the influence of intraocular pressure. Prog Retin Eye Res 22: 435–463.
[31]
Kommareddi PK, Nair TS, Raphael Y, Telian SA, Kim AH, et al. (2007) Cochlin isoforms and their interaction with CTL2 (SLC44A2) in the inner ear. J Assoc Res Otolaryngol 8: 435–446.
[32]
Lesage F, Lazdunski M (2000) Molecular and functional properties of two-pore-domain potassium channels. Am J Physiol Renal Physiol 279: F793–801.
[33]
Lauritzen I, Chemin J, Honore E, Jodar M, Guy N, et al. (2005) Cross-talk between the mechano-gated K2P channel TREK-1 and the actin cytoskeleton. EMBO Rep 6: 642–648.
[34]
Chemin J, Patel AJ, Duprat F, Lauritzen I, Lazdunski M, et al. (2005) A phospholipid sensor controls mechanogating of the K+ channel TREK-1. Embo J 24: 44–53.
[35]
Sharif-Naeini R, Folgering JH, Bichet D, Duprat F, Lauritzen I, et al. (2009) Polycystin-1 and -2 dosage regulates pressure sensing. Cell 139: 587–596.
[36]
Lambrechts A, Jonckheere V, Peleman C, Polet D, De Vos W, et al. (2006) Profilin-I-ligand interactions influence various aspects of neuronal differentiation. J Cell Sci 119: 1570–1578.
[37]
Syriani E, Gomez-Cabrero A, Bosch M, Moya A, Abad E, et al. (2008) Profilin induces lamellipodia by growth factor-independent mechanism. Faseb J 22: 1581–1596.
[38]
Morales M, Gomez-Cabrero A, Peral A, Gasull X, Pintor J (2007) Hypotensive effect of profilin on rabbit intraocular pressure. Eur J Pharmacol 567: 145–148.
[39]
Gomez-Cabrero A, Comes N, Gonzalez-Linares J, de Lapuente J, Borras M, et al. (2005) Use of transduction proteins to target trabecular meshwork cells: outflow modulation by profilin I. Mol Vis 11: 1071–1082.
[40]
Maepea O, Bill A (1992) Pressures in the juxtacanalicular tissue and Schlemm's canal in monkeys. Exp Eye Res 54: 879–883.
[41]
Tian B, Gabelt BT, Geiger B, Kaufman PL (2009) The role of the actomyosin system in regulating trabecular fluid outflow. Exp Eye Res 88: 713–717.
[42]
Zhang Y, Toris CB, Liu Y, Ye W, Gong H (2009) Morphological and hydrodynamic correlates in monkey eyes with laser induced glaucoma. Exp Eye Res 89: 748–756.
[43]
Gong H, Freddo TF (2009) The washout phenomenon in aqueous outflow–why does it matter? Exp Eye Res 88: 729–737.
[44]
Quigley HA, Broman AT (2006) The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90: 262–267.
[45]
Morrison JC, Johnson EC, Cepurna W, Jia L (2005) Understanding mechanisms of pressure-induced optic nerve damage. Prog Retin Eye Res 24: 217–240.
