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Abnormal basement membrane in the inner ear and the kidney of the Mpv17-/- mouse strain: ultrastructural and immunohistochemical investigations

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Abstract

The loss of the function of the peroxisomal Mpv17-protein and associated imbalanced radical oxygen species (ROS) homeostasis leads to an early onset of focal segmental glomerulosclerosis and sensorineural deafness associated with severe degeneration of cochlear structures. An excessive enlargement of basal laminae of the stria vascularis capillaries and glomeruli indicates numerous changes in their molecular composition. The basement membrane (BM) of the glomeruli and the stria vascularis are simultaneously affected in early stages of the disease and the lamination, splitting of the membrane and formation of the “basket weaving” seen at the onset of the disease in the kidney are similar to the ultrastructural alterations characteristic for Alportȁ9s syndrome. The progressive alteration of the BMs is accompanied by irregularity in the distribution of the collagen IV subunits and by an accumulation of the laminin B2(γ1) in the inner ear and B(β1) in the kidney. Since Mpv17 protein contributes to ROS homeostasis, further studies are necessary to elucidate downstream signaling molecules activated by ROS. These studies explain the cellular responses to missing Mpv17-protein, such as accumulation of the extracellular matrix, degeneration, and apoptosis in the inner ear.

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References

  • Abrahamson DR, Prettyman AC, Robert B, St John PL (2003) Laminin-1 reexpression in Alport mouse glomerular basement membranes. Kidney Int 63:826–834

    Article  PubMed  CAS  Google Scholar 

  • Binder CJ, Weiher H, Exner M, Kerjaschki D (1999) Glomerular overproduction of oxygen radicals in Mpv17 gene-inactivated mice causes podocyte foot processes flattening ad proteinuria. J Pathol 154:1067–1075

    CAS  Google Scholar 

  • Burgeson RE, Chiquet M, Deutzmann R, Ekblom P, Engel J, Kleinman H, Martin GR, Meneguzzi G, Paulsson M, Santes J, Timpl R, Trygggvason K, Yamada Y, Yurchenko PD (1994) A new nomenclature for the laminin. Matrix Biol 14:209–211

    Article  PubMed  CAS  Google Scholar 

  • Chai Q, Krag S, Miner JH, Neyengaard JR, Chai S, Wogensen L (2003) TGF-β1 induces aberrant laminin chain and collagen type IV isotype expression in the glomerular basement membrane. Nephron Exp Nephrol 94:123–136

    Article  CAS  Google Scholar 

  • Cosgrove D, Rodgers KD (1997) Expression of the major basement membrane-associated proteins during postnatal development in the murine cochlea. Hear Res 105:159–170

    Article  PubMed  CAS  Google Scholar 

  • Cosgrove D, Samuelson G, Pitt J (1996a) Immunohistochemical localization of basement membrane collagens and associated proteins in the murine cochlea. Hear Res 97:54–65

    Article  PubMed  CAS  Google Scholar 

  • Cosgrove D, Meehan DT, Grunkemeyer JA, Kornak JM, Sayers R, Hunter WJ, Samuelson GC (1996b) Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome. Genes Dev 10:2981–2992

    Article  PubMed  CAS  Google Scholar 

  • Cosgrove D, Samuelson GC, Meehan DT, Miller C, McGee J, Walsh EJ, Siegel M (1998) Ultrastructural, physiological and molecular defects in the inner ear of a gene-knockout mouse model for autosomal Alport syndrome. Hear Res 121:84–98

    Article  PubMed  CAS  Google Scholar 

  • Cosgrove D, Rodgers K, Meehan D, Miller C, Bovard K, Gilroy A, Gardner H, Kotelianski V, Gotwals P, Amatucci A, Kalluri R (2000) Integrin alpha1 beta1 and transforming growth factor-beta1 play distinct role in Alport glomerular pathogenesis and serve as dual target for metabolic therapy. Am J Pathol 157:1649–1659

    PubMed  CAS  Google Scholar 

  • Erickson AC, Couchman JR (2000) Still more complexity in mammalian basement membrane. J Histochem Cytochem 48:1291–1306

    PubMed  CAS  Google Scholar 

  • Fassin G, Ferrari N, Brigati C Benelli R, Santi L, Noonan DM, Albini A (2000) Tissue inhibitors of metaloproteinases: regulation and biological activities. Clin Exp Metastasis 18:111–120

    Article  PubMed  Google Scholar 

  • Gibson IW, More IAR (1998) Glomerular pathology: recent advances. J Pathol 184:123–129

    Article  PubMed  CAS  Google Scholar 

  • Gratton MA, Schulte BA (1995) Alterations in microvasculature are associated with atrophy of stria vascularis in quiet-aged gerbils. Hear Res 82:44–52

    Article  PubMed  CAS  Google Scholar 

  • Gratton MA, Schmied RA, Schulte BA (1996) Age-related decreases in endocochlear potential are associated with vascular abnormalities. Hear Res 102:181–190

    Article  PubMed  CAS  Google Scholar 

  • Gratton MA, Meekan DT, Smyth BJ, Cosgrove D (2002.) Strial marginal cells play a role in basement membrane homeostasis: in vitro and in vivo evidence. Hear Res 163:27–36

    Article  PubMed  CAS  Google Scholar 

  • Gross O, Beirowski B, Koepke ML, Kuck J, Reiner M, Addick K, Smyth N, Schulze-Lohoff, Weber M (2003) Preemptive ramipril therapy delay renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int 63:438–446

    Article  PubMed  CAS  Google Scholar 

  • Ha H, Lee HB (2001) Oxidative stress in diabetic nephropathy: basic and clinical information. Curr Diab Rep 1:282–287

    Article  PubMed  CAS  Google Scholar 

  • Iida R, Yasuda T, Tsubota E, Matsuki T, KishiK (2001) Cloning, mapping, genomic organization, and expression of mouse M-LP, a new member of peroxisomal membrane protein Mpv17 domain family. Biochem Biophys Res Commun 283:292–296

    Article  PubMed  CAS  Google Scholar 

  • Iida R, Yasuda T, Tsubota E, Takatsuka H, Masuyama M, Matsuki T, Kishi K (2002) M-LP. Mpv17-like protein, has a peroxisomal membrane targeting signal comprising a transmembrane domain and a positively charged loop and upregulates expression of the manganese superoxide dismutase gene. J Biol Chem 278:6301–6306

    Article  PubMed  Google Scholar 

  • Iida R, Yasuda T, Tsubota E, Takatsuka H, Masuyama M, Matsuki T, Kishi K (2005) A novel alternative spliced Mpv17-like protein isoform localizes in cytosol and is expressed in a kidney- and adult-specific manner. Exp Cell Res 302:22–30

    Article  PubMed  CAS  Google Scholar 

  • Izzedine H, Tankere F, Launay-Vacher W, Deray G (2004) Ear and kidney syndromes: molecular vs clinical approach. Kidney Int 65:369–385

    Article  PubMed  CAS  Google Scholar 

  • Kaldi K, Diestelkotter P, Stenbeck G, Aurbach S, Jakle U, Magert HJ, Wieland FT, Just WW (1993) Membrane topology of the 22 kDa integral peroxisomal membrane protein. FEBS Lett 315:217–222

    Article  PubMed  CAS  Google Scholar 

  • Kashtan CE (1999) Alport syndrome, an inherited disorder of renal, ocular, and cochlear basement membrane. Medicine 78:338–360

    Article  PubMed  CAS  Google Scholar 

  • Kashtan CE, Kim Y, Lees GE, Thorner PS, Vitrtanen I, Miner JH (2000) Abnormal glomerular basement membrane laminins in murine, canine and human Alport syndrome: aberrant laminin α2 deposition is species independent. J Am Soc Nephrol 12:252–260

    Google Scholar 

  • Mason RM, Wahab NA (2003) Extracellular matrix metabolism in diabetic nephropathy. J Nephrol 14:1358–1373

    Article  CAS  Google Scholar 

  • McGabe BF (1979) Autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol 88:585–589

    PubMed  Google Scholar 

  • McQueen CT, Baxter A, Smith TL, Raynor R, Yoon SM, Prazma J, Pillsbury HC (1999) Non insulin dependent diabetic microangiopathy in the inner ear. J Laryngol Otol 113:13–18

    PubMed  CAS  Google Scholar 

  • Merchant SN, Burgess BJ, Adams JC, Kashtan CE; Gregory MC, Santi PA, Colvin R, Collins B, Nadol JB (2004) Temporal bone histopathology in Alport syndrme. Laryngoscope 114:1609–1618

    Article  PubMed  Google Scholar 

  • Meyer zum Gottesbeger AM, Felix H, Reuter A, Weieher H (2001a) Ultrastructural and physiological effects in the cochlea of the Mpv17 mouse strain. A comparison between young and old adult animals. Hear Res 156:69–80

    Article  PubMed  Google Scholar 

  • Meyer zum Gottesberge AM, Reuter A, Weiher H (1996) Inner ear defect similar to Alportȁ9s syndrome in the glomerulosclerosis mouse model Mpv17. Eur Arch Otorhinolaryngol 253:470–474

    Article  PubMed  CAS  Google Scholar 

  • Meyer zum Gottesberge AM, Balz V, Felix H (2001b) Mpv17-/- mouse strain a model for the relationship between the kidney and the inner ear. Adv Otorhinolaryngol 59:84–90

    Google Scholar 

  • Miner JH (2003) A molecular look at the glomerular barrier. Nephron Exp Nephrol 94:119–122

    Article  Google Scholar 

  • Miner JH, Sanes JS (1996) Molecular and functional defects in kidneys of mice lacking collagen α3(IV): implications for Alport syndrome. J Cell Biol 135:1403–1413

    Article  PubMed  CAS  Google Scholar 

  • Miner JH, Yurchenco PD (2004) Laminin functions in tissue morphogenesis. Annu Rev Cell Dev Biol 20:155–284

    Article  CAS  Google Scholar 

  • Müller M, Smolders JWT, Meyer zum Gottesberge AM, Reuter A, Zwacka RM, Weiher H, Klinke R (1997) Loss of auditory function in transgenic Mpv17-deficient mice. Hear Res 114:259–263

    Article  PubMed  Google Scholar 

  • Noakes PG, Minner JH, Gautam M, Cunningham JM, Santes JR, Merlie JP (1995) The renal glomerulus of mice lacking s-laminin/laminin beta2: nephrosis despite molecular compensation by laminin beta1. Nat Genet 10:400–406

    Article  PubMed  CAS  Google Scholar 

  • Oȁ9Bryan T, Weiher H, Rennke HG, Kren S, Hostetter TH (2000) Course of renal injury in the Mpv17-deficient transgenic mouse. J Am Soc Nephrol 11:1067–1074

    PubMed  Google Scholar 

  • Peters TA, Monnens LAH, Cremers CWRJ, Curfs JHAJ (2004) Genetic disorders of transporters/channels in the inner ear and their relation to the kidney. Pediatr Nephrol 19:1194–1201

    Article  PubMed  Google Scholar 

  • Rao VH, Lees GE, Kashtan CE, Nemori R, Singh RK, Meehan DT, Rodgers K, Berridge BR, Bhattacharya G, Cosgrove D (2003) Increased expression of MMp-2, MMP-9 (type IV collagenase/gelatinase), and MTI– mMP in canine X-linked Alport syndrome (XLAS). Kidney Int 63:1736–1748

    Article  PubMed  CAS  Google Scholar 

  • Reuter A, Nestl A, Zwacka RM, Tuckermann J, Waldherr R, Wagner EM, Höyhtyä, M, Meyer zum Gottesberge AM, Angel P, Weiher H (1998) Expression of the recessive glomerulosclerosis gene Mpv17 regulates MMP-2 expression in fibroblasts, the kidney and the inner ear. Mol Biol Cell 9:1675–1682

    PubMed  CAS  Google Scholar 

  • Rodgers KD, Barrit L, Miner JH, Cosgrove D (2001) The laminins in the murine inner ear: developmental transitions and expression in cochlear basement membranes. Hear Res 158:39–50

    Article  PubMed  CAS  Google Scholar 

  • Rohrmoser MM, Mayer G (1996) Reactive oxygen species and glomerular injury. Kidney Blood Press Res 19:263–269

    Article  PubMed  CAS  Google Scholar 

  • Sakagutchi N, Spicer SS, Thomopoulos GN, Schulte BA (1997) Immunoglobulin deposition in thickened basement membranes of aging strial capillaries. Hear Res 109:83–91

    Article  PubMed  Google Scholar 

  • Sayers R, Kalluri R, Rodgers KD, Shield CF, Meeehan T, Cosgrove D (2001) Role for transforming growth factor-β1 in Alport renal disease progression. Kidney Int 56:1662–1673

    Article  Google Scholar 

  • Schucknecht HF (1974) Developmental defects. In: Pathology of the ear. Harvard University Press, Cambridge, MA, pp165–213

  • Slepecky N (1996) Structure of the mammalian cochlea. In: Dallos P, Popper AN, Fay RR (eds) The cochlea. Springer, Berlin Heidelberg New York, pp 44–129

    Google Scholar 

  • Smith TL, Raynir E, Prazma J, Buenting JE, Piilsbury HC III (1995) Insulin dependent diabetic microangiopathy in the inner ear. Laryngoscope 105:236–240

    Article  PubMed  CAS  Google Scholar 

  • Strauß P, Schmittner S, Rick W, Fassbender-Balg S (1982) Inner ear and diabetes mellitus diabetic mutant mice. Laryngol Rhinol Otol 61:325–330

    Google Scholar 

  • Thomopoulos GN, Spicer SS, Gratton MA, Schulte BA (1997) Age-related thickening of basement membrane in stria vascularis capillaries. Hear Res 111:31–41

    Article  PubMed  CAS  Google Scholar 

  • Timpl R, Brown JC (1996) The laminins. Matrix Biol 14:275–281

    Article  Google Scholar 

  • Tokahashi M, Hokunan K (1992) Localization of type IV collagen and laminin in the guinea pig inner ear. Ann Otol Rhinol Laryngol 191:58–62

    Google Scholar 

  • Tsupran V, Santi P (1999) Ultrastructure and immunohistochemical identification of the extracellular matrix of the chinchilla cochlea. Hear Res 129:35–49

    Article  PubMed  Google Scholar 

  • Tsupran V, Santi P (2001) Proteoglycan arrays in the cochlear basement membrane. Hear Res 175:65–76

    Article  Google Scholar 

  • Tunggal P, Smyth N, Paulsson M, Ott MC (2000) Laminins: structure and genetic regulation. Microsc Res Tech 51:214–227

    Article  PubMed  CAS  Google Scholar 

  • Wagner G, Stettmaier K, Bors W, Sies H, Wagner EM, Reuter A, Weiher H (2001) Enhanced gamma-glutamyl transpeptidase expression and superoxide production in Mpv17-/-glomerulosclerosis mice. Biol Chem 382:1019–1025

    Article  PubMed  CAS  Google Scholar 

  • Weidauer H, Arnold A (1976) Structurelle Veränderungen am Hörorgan beim Alport Syndrom. Z Laryngol Rhinol Otol 55:6–16

    CAS  Google Scholar 

  • Weiher H, Noda T, Gray DA, Sharpe AH, Jaenisch R (1990) Transgenic mouse model of kidney disease: insertional inactivation of ubiquitously expressed gene leads to nephrotic syndrome. Cell 62:425–434

    Article  PubMed  CAS  Google Scholar 

  • Weinberger DG, ten-Cate WJ, Lautermann J, Baethmann M (1999) Lacalization of laminin isoforms in the guinea pig cochlea. Laryngoscope 109:201–204

    Article  Google Scholar 

  • Yoshizaki T, Sato H, Furukawa M (2002) Recent advances in the regulation of matrix metalloproteinas 2 activation: from basic research to clinical implication (review). Oncol Rep 9:607–611

    PubMed  CAS  Google Scholar 

  • Yurchenko PD, Schittny JS (1990) Molecular architecture of basement membranes. FASEB J 4:1577–1590

    PubMed  Google Scholar 

  • Zwacka R, Reuter A, Pfaff E, Moll J, Gorgas K, Karasawa M, Weiher H (1994) The glomerulosclerosis gene Mpv17 encodes a peroxisomal protein producing reactive oxygen species. EMBO J 13:5129–5134

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors wish to thank Mrs. V. Hoffmann (Zürich) and U. Becker-Lendzian for their excellent technical help, Mrs.Trenker for the care of the animal and Dr. M.A. Gratton (University of Pennsylvania) for critical comments to the manuscript. Also we would like to acknowledge Dr. J. Miner Washington University for providing rabbit anti-novel chains collagen 4A3, 4A4, and 4A5 antibodies.

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  1. Research Laboratory, Department of Otorhinolaryngology, University of Düsseldorf, Moorenstr, 5, 40225, Dusseldorf, Germany

    Angela M. Meyer zum Gottesberge

  2. Department of Otorhinolaryngology, University Hospital, Zurich, Switzerland

    Heidi Felix

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  1. Angela M. Meyer zum Gottesberge
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Correspondence to Angela M. Meyer zum Gottesberge.

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Meyer zum Gottesberge, A.M., Felix, H. Abnormal basement membrane in the inner ear and the kidney of the Mpv17-/- mouse strain: ultrastructural and immunohistochemical investigations. Histochem Cell Biol 124, 507–516 (2005). https://doi.org/10.1007/s00418-005-0027-7

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