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Human TTRV30M localization within podocytes in a transgenic mouse model of transthyretin related amyloidosis: does the environment play a role?

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Abstract

Transthyretin related amyloidosis is a nosological entity that leads to disability, diminished quality of life, all stages of chronic kidney disease and eventually death. Podocytes are polarized, highly differentiated epithelial cells important for proper nephron function. In the present study we investigated whether deposited TTRVal30Met (TTRV30M) molecules could be localized within podocytes in situ under the effect of different housing conditions (i.e. specific pathogen free [SPF] vs. non-SPF). Murine renal glomeruli from human TTRV30M (hTTRV30M) transgenic mice were examined via direct and indirect immunofluorescence techniques for the presence of hTTRV30M, murine serum amyloid P, activated caspase-3 and NPHS1. Association strength and amount of colocalization for NPHS1–hTTRV30M, NPHS1-activated caspase-3, hTTRV30M-murine serum amyloid P were estimated. Localization of hTTRV30M in podocytes was demonstrated by immuno-electron microscopy. Renal hTTRV30M gene and NPHS1 gene expression levels were estimated. Non-SPF transgenic mice showed increased glomerular hTTRV30M deposition compared to their SPF counterparts. Furthermore increased podocytic localization of hTTRV30M was noticed in non-SPF mice. Glomerular caspase-3 activation was increased only in the non SPF housing conditions. Podocytic caspase-3 activation was increased in SPF and in non-SPF transgenic mice when compared to non transgenic controls. Environmental conditions influence glomerular deposition and podocytic localization of hTTRV30M. In this context increased caspase-3 activation occurred.

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References

  • Alcorn D, Ryan GB (1993) The glomerular peripolar cell. Kidney Int Suppl 42:S35–S39

    PubMed  CAS  Google Scholar 

  • Benson MD, Kincaid JC (2007) The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve 36(4):411–423

    Article  PubMed  CAS  Google Scholar 

  • Bolte S, Cordelières FP (2006) A guided tour into subcellular colocalization analysis in light microscopy. J Microsc 224(Pt 3):213–232

    Article  PubMed  CAS  Google Scholar 

  • Bondeva T, Wojciech S, Wolf G (2011) Advanced glycation end products inhibit adhesion ability of differentiated podocytes in a neuropilin-1-dependent manner. Am J Physiol Renal Physiol 301(4):F852–F870

    Article  PubMed  CAS  Google Scholar 

  • Brown JK, Pemberton AD, Wright SH, Miller HR (2004) Primary antibody-Fab fragment complexes: a flexible alternative to traditional direct and indirect immunolabeling techniques. J Histochem Cytochem 52(9):1219–1230

    Article  PubMed  CAS  Google Scholar 

  • Cardoso I, Saraiva MJ (2006) Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model. FASEB J 20(2):234–239

    Article  PubMed  CAS  Google Scholar 

  • Castaño AP, Lin SL, Surowy T, Nowlin BT, Turlapati SA, Patel T, Singh A, Li S, Lupher ML, Duffield JS (2009) Serum amyloid P inhibits fibrosis through Fc gamma R-dependent monocyte-macrophage regulation in vivo. Sci Transl Med 1(5):5ra13

    Article  PubMed  Google Scholar 

  • Chuang PY, Dai Y, Liu R, He H, Kretzler M, Jim B, Cohen CD, He JC (2011) Alteration of forkhead box O (foxo4) acetylation mediates apoptosis of podocytes in diabetes mellitus. PLoS One 6(8):e23566

    Article  PubMed  CAS  Google Scholar 

  • Dorak T (2006) Real-time PCR, BIOS advanced methods. Taylor & Francis, New York

    Google Scholar 

  • Dyck RF, Lockwood CM, Kershaw M, McHugh N, Duance VC, Baltz ML, Pepys MB (1980) Amyloid P-component is a constituent of normal human glomerular basement membrane. J Exp Med 152(5):1162–1174

    Article  PubMed  CAS  Google Scholar 

  • Eirin A, Irazabal MV, Gertz MA, Dispenzieri A, Lacy MQ, Kumar S, Sethi S, Nasr SH, Cornell LD, Fidler ME, Fervenza FC, Leung N (2012) Clinical features of patients with immunoglobulin light chain amyloidosis (AL) with vascular-limited deposition in the kidney. Nephrol Dial Transpl 27(3):1097–1101

    Google Scholar 

  • Fleming CE, Mar FM, Franquinho F, Saraiva MJ, Sousa MM (2009) Transthyretin internalization by sensory neurons is megalin mediated and necessary for its neuritogenic activity. J Neurosci 29(10):3220–3232

    Article  PubMed  CAS  Google Scholar 

  • Gervais FG, Thornberry NA, Ruffolo SC, Nicholson DW, Roy S (1998) Caspases cleave focal adhesion kinase during apoptosis to generate a FRNK-like polypeptide. J Biol Chem 273(27):17102–17108

    Article  PubMed  CAS  Google Scholar 

  • Holmgren G, Wikström L, Lundgren HE, Suhr OB (2004) Discordant penetrance of the trait for familial amyloidotic polyneuropathy in two pairs of monozygotic twins. J Intern Med 256(5):453–456

    Article  PubMed  CAS  Google Scholar 

  • Inoue S, Ohta M, Li Z, Zhao G, Takaoka Y, Sakashita N, Miyakawa K, Takada K, Tei H, Suzuki M, Masuoka M, Sakaki Y, Takahashi K, Yamamura K (2008) Specific pathogen free conditions prevent transthyretin amyloidosis in mouse models. Transgenic Res 17(5):817–826

    Article  PubMed  CAS  Google Scholar 

  • Jennette JC, Heptinstall RH (2007) Heptinstall’s pathology of the kidney, 6th edn. Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  • Jeruc J, Vizjak A, Rozman B, Ferluga D (2006) Immunohistochemical expression of activated caspase-3 as a marker of apoptosis in glomeruli of human lupus nephritis. Am J Kidney Dis 48(3):410–418

    Article  PubMed  CAS  Google Scholar 

  • Kaysen GA (2001) The microinflammatory state in uremia: causes and potential consequences. J Am Soc Nephrol 12(7):1549–1557

    PubMed  CAS  Google Scholar 

  • Lee LK, Pollock AS, Lovett DH (1993) Asymmetric origins of the mature glomerular basement membrane. J Cell Physiol 157(1):169–177

    Article  PubMed  CAS  Google Scholar 

  • Liu XL, Kilpeläinen P, Hellman U, Sun Y, Wartiovaara J, Morgunova E, Pikkarainen T, Yan K, Jonsson AP, Tryggvason K (2005) Characterization of the interactions of the nephrin intracellular domain. FEBS J 272(1):228–243

    Article  PubMed  CAS  Google Scholar 

  • Lobato L, Beirão I, Silva M, Bravo F, Silvestre F, Guimarães S, Sousa A, Noël LH, Sequeiros J (2003) Familial ATTR amyloidosis: microalbuminuria as a predictor of symptomatic disease and clinical nephropathy. Nephrol Dial Transplant 18(3):532–538

    Article  PubMed  CAS  Google Scholar 

  • Lobato L, Beirão I, Silva M, Fonseca I, Queirós J, Rocha G, Sarmento AM, Sousa A, Sequeiros J (2004) End-stage renal disease and dialysis in hereditary amyloidosis TTR V30M: presentation, survival and prognostic factors. Amyloid 11(1):27–37

    Article  PubMed  Google Scholar 

  • Lundmark K, Westermark GT, Olsén A, Westermark P (2005) Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: cross-seeding as a disease mechanism. Proc Natl Acad Sci USA 102(17):6098–6102

    Article  PubMed  CAS  Google Scholar 

  • Macedo B, Magalhães J, Batista AR, Saraiva MJ (2010) Carvedilol treatment reduces transthyretin deposition in a familial amyloidotic polyneuropathy mouse model. Pharmacol Res 62(6):514–522

    Article  PubMed  CAS  Google Scholar 

  • Marshall CB, Krofft RD, Blonski MJ, Kowalewska J, Logar CM, Pippin JW, Kim F, Feil R, Alpers CE, Shankland SJ (2011) Role of smooth muscle protein SM22α in glomerular epithelial cell injury. Am J Physiol Renal Physiol 300(4):F1026–F1042

    Article  PubMed  CAS  Google Scholar 

  • Matsunaga N, Anan I, Rosenberg P, Nagai R, Lundström O, Horiuchi S, Ando Y, Suhr OB (2005) Advanced glycation end product is implicated in amyloid-related kidney complications. Scand J Clin Lab Invest 65(4):263–271

    Article  PubMed  CAS  Google Scholar 

  • Miner JH (2011) Organogenesis of the kidney glomerulus: focus on the glomerular basement membrane. Organogenesis 7(2):75–82

    Article  PubMed  Google Scholar 

  • Misumi Y, Ueda M, Obayashi K, Jono H, Su Y, Yamashita T, Ohshima T, Ando Y, Uchino M (2012) Relationship between amyloid deposition and intracellular structural changes in familial amyloidotic polyneuropathy. Hum Pathol 43(1):96–104

    Article  PubMed  CAS  Google Scholar 

  • Mundel P, Kriz W (1995) Structure and function of podocytes: an update. Anat Embryol (Berl) 192(5):385–397

    Article  CAS  Google Scholar 

  • Nagata Y, Tashiro F, Yi S, Murakami T, Maeda S, Takahashi K, Shimada K, Okamura H, Yamamura K (1995) A 6-kb upstream region of the human transthyretin gene can direct developmental, tissue-specific, and quantitatively normal expression in transgenic mouse. J Biochem 117(1):169–175

    PubMed  CAS  Google Scholar 

  • Noguchi H, Ohta M, Wakasugi S, Noguchi K, Nakamura N, Nakamura O, Miyakawa K, Takeya M, Suzuki M, Nakagata N, Urano T, Ono T, Yamamura K (2002) Effect of the intestinal flora on amyloid deposition in a transgenic mouse model of familial amyloidotic polyneuropathy. Exp Anim 51(4):309–316

    Article  PubMed  CAS  Google Scholar 

  • Pepys M, Booth D, Hutchinson W, Gallimore J, Collins P, Hohenester E (1997) Amyloid P component. A critical review. Amyloid 4(4):274–295

    Article  CAS  Google Scholar 

  • Porter AG, Jänicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6(2):99–104

    Article  PubMed  CAS  Google Scholar 

  • Prabakaran T, Nielsen R, Larsen JV, Sørensen SS, Feldt-Rasmussen U, Saleem MA, Petersen CM, Verroust PJ, Christensen EI (2011) Receptor-mediated endocytosis of α-galactosidase A in human podocytes in Fabry disease. PLoS One 6(9):e25065

    Article  PubMed  CAS  Google Scholar 

  • Putaala H, Soininen R, Kilpeläinen P, Wartiovaara J, Tryggvason K (2001) The murine nephrin gene is specifically expressed in kidney, brain and pancreas: inactivation of the gene leads to massive proteinuria and neonatal death. Hum Mol Genet 10(1):1–8

    Article  PubMed  CAS  Google Scholar 

  • Rapezzi C, Quarta CC, Riva L, Longhi S, Gallelli I, Lorenzini M, Ciliberti P, Biagini E, Salvi F, Branzi A (2010) Transthyretin-related amyloidoses and the heart: a clinical overview. Nat Rev Cardiol 7(7):398–408

    Article  PubMed  CAS  Google Scholar 

  • Sambrook J, Russell DW (2006) The condensed protocols from Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor

    Google Scholar 

  • Schreiber G, Richardson SJ (1997) The evolution of gene expression, structure and function of transthyretin. Comp Biochem Physiol B Biochem Mol Biol 116(2):137–160

    Article  PubMed  CAS  Google Scholar 

  • Shkreli M, Sarin KY, Pech MF, Papeta N, Chang W, Brockman SA, Cheung P, Lee E, Kuhnert F, Olson JL, Kuo CJ, Gharavi AG, D’Agati VD, Artandi SE (2012) Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling. Nat Med 18(1):111–119

    Article  CAS  Google Scholar 

  • Soares ML, Coelho T, Sousa A, Batalov S, Conceição I, Sales-Luís ML, Ritchie MD, Williams SM, Nievergelt CM, Schork NJ, Saraiva MJ, Buxbaum JN (2005) Susceptibility and modifier genes in Portuguese transthyretin V30M amyloid polyneuropathy: complexity in a single-gene disease. Hum Mol Genet 14(4):543–553

    Article  PubMed  CAS  Google Scholar 

  • Sobue G, Koike H, Misu K, Hattori N, Yamamoto M, Ikeda S, Ando Y, Nakazato M, Inukai A (2003) Clinicopathologic and genetic features of early- and late-onset FAP type I (FAP ATTR Val30Met) in Japan. Amyloid 10(Suppl 1):32–38

    PubMed  CAS  Google Scholar 

  • Sousa MM, Cardoso I, Fernandes R, Guimarães A, Saraiva MJ (2001a) Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy: evidence for toxicity of nonfibrillar aggregates. Am J Pathol 159(6):1993–2000

    Article  PubMed  CAS  Google Scholar 

  • Sousa MM, Du Yan S, Fernandes R, Guimaraes A, Stern D, Saraiva MJ (2001b) Familial amyloid polyneuropathy: receptor for advanced glycation end products-dependent triggering of neuronal inflammatory and apoptotic pathways. J Neurosci 21(19):7576–7586

    PubMed  CAS  Google Scholar 

  • Stangou AJ, Banner NR, Hendry BM, Rela M, Portmann B, Wendon J, Monaghan M, Maccarthy P, Buxton-Thomas M, Mathias CJ, Liepnieks JJ, O’Grady J, Heaton ND, Benson MD (2010) Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation. Blood 115(15):2998–3007

    Article  PubMed  CAS  Google Scholar 

  • Stylianou K, Petrakis I, Mavroeidi V, Stratakis S, Vardaki E, Perakis K, Stratigis S, Passam A, Papadogiorgaki E, Giannakakis K, Nakopoulou L, Daphnis E (2011) The PI3K/Akt/mTOR pathway is activated in murine lupus nephritis and downregulated by rapamycin. Nephrol Dial Transpl 26(2):498–508

    Article  CAS  Google Scholar 

  • Susztak K, Raff AC, Schiffer M, Böttinger EP (2006) Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55(1):225–233

    Article  PubMed  CAS  Google Scholar 

  • Tagoe CE, Jacobson DR, Gallo G, Buxbaum JN (2003) Mice transgenic for human TTR have the same frequency of renal TTR deposition whether maintained in conventional or specific pathogen free environments. Amyloid 10(4):262–266

    Article  PubMed  CAS  Google Scholar 

  • Teng MH, Yin JY, Vidal R, Ghiso J, Kumar A, Rabenou R, Shah A, Jacobson DR, Tagoe C, Gallo G, Buxbaum J (2001) Amyloid and nonfibrillar deposits in mice transgenic for wild-type human transthyretin: a possible model for senile systemic amyloidosis. Lab Invest 81(3):385–396

    Article  PubMed  CAS  Google Scholar 

  • Tomiyoshi G, Horita Y, Nishita M, Ohashi K, Mizuno K (2004) Caspase-mediated cleavage and activation of LIM-kinase 1 and its role in apoptotic membrane blebbing. Genes Cells 9(6):591–600

    Article  PubMed  CAS  Google Scholar 

  • Verine J, Mourad N, Desseaux K, Vanhille P, Noël LH, Beaufils H, Grateau G, Janin A, Droz D (2007) Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response. Hum Pathol 38(12):1798–1809

    Article  PubMed  Google Scholar 

  • Vieira AV, Sanders EJ, Schneider WJ (1995) Transport of serum transthyretin into chicken oocytes. A receptor-mediated mechanism. J Biol Chem 270(7):2952–2956

    Article  PubMed  CAS  Google Scholar 

  • Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, Maiguel D, Karumanchi SA, Yap HK, Saleem M, Zhang Q, Nikolic B, Chaudhuri A, Daftarian P, Salido E, Torres A, Salifu M, Sarwal MM, Schaefer F, Morath C, Schwenger V, Zeier M, Gupta V, Roth D, Rastaldi MP, Burke G, Ruiz P, Reiser J (2011) Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 17(8):952–960

    Article  PubMed  CAS  Google Scholar 

  • Westermark GT, Johnson KH, Westermark P (1999) Staining methods for identification of amyloid in tissue. Methods Enzymol 309:3–25

    Article  PubMed  CAS  Google Scholar 

  • Westermark P, Benson MD, Buxbaum JN, Cohen AS, Frangione B, Ikeda S, Masters CL, Merlini G, Saraiva MJ, Sipe JD, Amyloidosis, N. C. o. t. I. S. o (2005) Amyloid: toward terminology clarification. Report from the nomenclature committee of the international society of amyloidosis. Amyloid 12(1):1–4

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Nephrology, Heraklion University Hospital, University of Crete, PO Box 1352, 71110, Heraklion, Crete, Greece

    Ioannis Petrakis, Vasiliki Mavroeidi, Kostas Stylianou, George Efthymiou, Kostas Perakis, Eleftheria Vardaki, Spyridon Stratigis & Eugene Daphnis

  2. Department of Radiology, Oncology and Pathology, Sapienza University of Rome, Rome, Italy

    Kostas Giannakakis

  3. Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology Heraklion, Heraklion, Crete, Greece

    Kostas Kourouniotis

  4. Department of Neurology, University of Crete, Heraklion, Greece

    George Amoiridis & Andreas Plaitakis

  5. Institute for Cellular and Molecular Biology, Porto, Portugal

    Maria Joao Saraiva

  6. Institute for Resources Development and Analysis, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan

    Ken Ichi Yamamura

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  1. Ioannis Petrakis
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Petrakis, I., Mavroeidi, V., Stylianou, K. et al. Human TTRV30M localization within podocytes in a transgenic mouse model of transthyretin related amyloidosis: does the environment play a role?. Transgenic Res 22, 101–116 (2013). https://doi.org/10.1007/s11248-012-9632-0

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