Skip to main content
SpringerLink
Log in

Cysteamine prevents inhibition of adenylate kinase caused by cystine in rat brain cortex

  • Original Paper
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Cystinosis is a systemic genetic disease caused by a lysosomal transport deficiency accumulating cystine in the lysosomes of almost all tissues. Although tissue damage might depend on cystine accumulation, the mechanisms of tissue damage are still obscures. Adenylate kinase, along with creatine kinase, is responsible for the enzymatic phosphotransfer network, crucial for energy homeostasis. Taking into account that cystine is known to inhibit creatine kinase activity, the two enzymes have thiol groups, and the strong interaction between the two activities, our main objective was to investigate the effect of cystine on adenylate kinase activity in the brain cortex of Wistar rats. For the in vivo studies, the animals were injected twice a day with 1.6 μmol/g body weight of cystine dimethylester and/or 0.46 μmol/g body weight of cysteamine from the 25th to the 29th postpartum day and sacrificed after 12 h. Cystine inhibited the enzyme activity in vitro in a concentration dependent way, whereas cysteamine prevented the inhibition. Adenylate kinase activity was found diminished in the brain cortex of rats loaded with cystine dimethylester and co-administration of cysteamine prevented the diminution of the enzyme activity. Considering that adenylate kinase together with creatine kinase is crucial for energy homeostasis, the release of cystine from lysosomes with consequent enzymes inhibition could impair energy homeostasis, contributing to tissue damage in patients with cystinosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Ben-Nun A, Bashan N, Potashnik R, Cohen-luria R, Moran A (1992) Cystine dimethyl ester reduces the forces driving sodium-dependent transport in Llc-Pk1 cells. Am J Physiol 263:C516–C520

    PubMed  CAS  Google Scholar 

  • Ben-Nun A, Bashan N, Potashnik R, Cohen-Luria R, Moran A (1993) Cystine loading induces Fanconi’s syndrome in rats: in vivo and vesicle studies. Am J Physiol 265:839–844

    Google Scholar 

  • Burlacu A, Jinga V, Gafencu AV, Simionescu M (2001) Severity of oxidative stress generates different mechanisms of endothelial cell death. Cell Tissue Res 306:409–416

    Article  PubMed  CAS  Google Scholar 

  • Çcetinkaya I, Schlatter E, Hirsch JR, Herter P, Harms E, Kleta R (2002) Inhibition of Na+-dependent transporters in cystine-loaded human renal cells: electrophysiological studies on the Fanconi syndrome of cystinosis. J Am Soc Nephrol 13:2085–2093

    Article  CAS  Google Scholar 

  • Coor C, Salmon RF, Quigley R, Marver D, Baum M (1991) Role of adenosine- triphosphate (ATP) and Na+, K+ -ATPase in the inhibition of proximal tubule transport with intracellular cystine loading. J Clin Invest 87:955–961

    Article  PubMed  CAS  Google Scholar 

  • Das UN (2006) Pyruvate is an endogenous anti-inflammatory and anti-oxidant molecule. Med Sci Monit 12:RA79–RA84

    PubMed  CAS  Google Scholar 

  • Dzeja PP, Terzic A (2003) Phosphotransfer networks and cellular energetics. J Exp Biol 206:2039–2047

    Article  PubMed  CAS  Google Scholar 

  • Dzeja PP, Vitkevicius KT, Redfield MM, Burnettm JC, Terzic A (1999) Adenylate kinase–catalyzed phosphotransfer in the myocardium: increased contribution in heart failure. Circ Res 84:1137–1143

    PubMed  CAS  Google Scholar 

  • Dzeja PP, Bortolon R, Perez-Terzic C, Holmuhamedov EL, Terzic A (2002) Energetic communication between mitochondria and nucleus directed by catalyzed phosphotransfer. Proc Natl Acad Sci USA 99:10156–10161

    Article  PubMed  CAS  Google Scholar 

  • Feksa LR, Cornelio A, Dutra-Filho CS, Wyse ATS, Wajner M, Wannmacher CMD (2004) Inhibition of pyruvate kinase activity by cystine in brain cortex of rats. Brain Res 1012:93–100

    Article  PubMed  CAS  Google Scholar 

  • Fleck RMM, Rodrigues-Junior V, Giacomazzi J, Parissoto D, Dutra-Filho CS, Wyse ATS, Wajner M, Wannmacher CMD (2005) Cysteamine prevents and reverses the inhibition of creatine kinase activity caused by cystine in rat brain cortex. Neurochem Int 46:391–397

    Article  PubMed  CAS  Google Scholar 

  • Foreman JW, Bowring MA, Lee J, States B, Segal S (1987) Effect of cystine dimethyl ester on renal solute handling and isolated renal tubule transport in the rat: a new model Fanconi syndrome. Metab 36:1185–1191

    Article  CAS  Google Scholar 

  • Foreman JW, Benson LL, Wellons M, Avner ED, Sweeney W, Nissim I, Nissim I (1995) Metabolic studies of rat renal tubule cells loaded with cystine: the cystine dimethylester model of cystinosis. J AmSoc Nephrol 6:269–272

    CAS  Google Scholar 

  • Gahl WA (2003) Early oral cysteamine therapy for nephropathic cystinosis. Eur J Pediatr 162(1):38–41

    Article  CAS  Google Scholar 

  • Gahl WA, Thoene JG, Schneider JA (2001) Cystinosis: a disorder of lysosomal membrane transport. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic & Molecular Bases of Inherited Diseases. McGraw-Hill, New York, pp 5085–5108

    Google Scholar 

  • Gahl WA, Thoene JG, Schneider JA (2002) Cystinosis. N. Engl. J. Med. 347:111–121

    Article  PubMed  Google Scholar 

  • Gonzalez FB, Llesuy S, Boveris A (1991) Hydroperoxide initiated chemiluminescence: an assay for oxidative stress in biopsies of heart, liver, and muscle. Free Radic Biol Med 10:93–100

    Article  Google Scholar 

  • Kessler A, Biasibetti M, da Silva Melo DA, Wajner M, Dutra-Filho CS, Wyse ATS, Wannmacher CMD (2008) Antioxidant effect of cysteamine in brain cortex of young rats. Neurochem Res 33:737–744

    Article  PubMed  CAS  Google Scholar 

  • Laube GF, Shah V, Stewart VC, Hargreaves IP, Haq MR, Heales SJ, van’t Hoff WG (2006) Glutathione depletion and increased apoptosis rate in human cystinotic proximal tubular cells. Pediatr Nephrol 21:503–509

    Article  PubMed  Google Scholar 

  • Leech NL, Barrett KC, Morgan GA (2005) SPSS for intermediate statistics. Use and interpretation, Lawrence Erlbaum Associates Publishers (ed), London, pp 46–62

    Google Scholar 

  • Levtchenko EN, Wilmer MJG, Janssen AJM, Koenderink JB, Levtchenko EN, Wilmer MJG, Janssen AJM, Koenderink JB, Visch AJ, Willems PH, Graaf-Hess A, Blom HJ, van den Heuvel LP, Monnens LA (2006) Decreased ATP content and intact mitochondrial energy generating capacity in human cystinotic fibroblasts. Pediatr Res 59:287–292

    Article  PubMed  CAS  Google Scholar 

  • Llesuy SF, Milei J, Molina H (1985) Comparison of lipid peroxidation and myocardial damage induced by adriamycin and 40-epiadriamycin in mice. Tumori 71(3):241–249

    PubMed  CAS  Google Scholar 

  • Lloyd JB (1986) Disulphide reduction in lysosomes. The role of cysteine. Biochem J 237(1):271–272

    PubMed  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  • Oliveira PRP, Rodrigues-Junior V, Rech VC, Wannmacher CMD (2007) Cystine inhibits creatine kinase activity in pig retina. Arch Med Res 38:164–169

    Article  CAS  Google Scholar 

  • Oliver IT (1955) A spectrophotometric method for the determination of creatine phosphokinase and myokinase. Biochem J 61(1):116–122

    PubMed  CAS  Google Scholar 

  • Park MA, Thoene JG (2005) Potential role of apoptosis in development of the cystinotic phenotype. Pediatr Nephrol 20:441–446

    Article  PubMed  Google Scholar 

  • Pisoni RL, Park GY, Velilla VQ, Thoene JG (1995) Detection and characterization of a transport system mediating cysteamine entry into human fibroblast lysosomes. Specificity for aminoethylthiol and aminoethylsulfide derivatives. J Biol Chem 270:1179–1184

    Article  PubMed  CAS  Google Scholar 

  • Price NC, Cohn M, Schirmer RH (1975) Fluorescent and spin label probes of the environments of the sulfhydryl groups of porcine muscle adenylate kinase. J Biol Chem 250:644–652

    PubMed  CAS  Google Scholar 

  • Pucar D, Janssen E, Dzeja PP, Juranic N, Macura S, Wieringa B, Terzic A (2000) Compromised energetics in the adenylate kinase AK1 gene knockout heart under metabolic stress. J Biol Chem 275:41424–41429

    Article  PubMed  CAS  Google Scholar 

  • Rech VC, Feksa LR, Amaral MFA, Koch GW, Wajner M, Dutra-Filho CS, Wyse ATS, Wannmacher CMD (2007) Promotion of oxidative stress in kidney of rats loaded with cystine dimethyl ester. Pediatr Nephrol 22:1121–1128

    Article  PubMed  Google Scholar 

  • Rosa TG, Wyse ATS, Wajner M, Wannmacher CMD (2004) Cysteamine prevents and reverses the inhibition of pyruvate kinase activity caused by cystine in rat heart. Biochim Biophys Acta 1689:114–119

    PubMed  CAS  Google Scholar 

  • Salmon RF, Baum M (1990) Intracellular cystine loading inhibits transport in the rabbit proximal convoluted tubule. J Clin Invest 85:340–344

    Article  PubMed  CAS  Google Scholar 

  • Town M, Jean G, Cherqui S, Attard M, Forestier L, Whitmore S, Callen D, Gribouval O, Broyer M, Bates G, van’t Hoff W, Antignac C (1998) A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet 18:319–324

    Article  PubMed  CAS  Google Scholar 

  • Weeds AG, Noda L (1968) Amino acid sequences around the thiol groups of myokinase. Biochem J 107:311–312

    PubMed  CAS  Google Scholar 

  • Willemoes M, Kilstrup M (2005) Nucleoside triphosphate synthesis catalysed by adenylate kinase is ADP dependent. Arch Biochem Biophys 444:195–199

    Article  PubMed  CAS  Google Scholar 

  • Wilmer MJ, de Graaf-Hess A, Blom HJ, Dijkman HB, Monnens LA, van den Heuvel LP, Levtchenko EM (2005) Elevated oxidized glutathione in cystinotic proximal tubular epithelial cells. Biochem Biophys Res Commun 337:610–614

    Article  PubMed  CAS  Google Scholar 

  • Wilmer MJ, Willems PH, Verkaart S, Visch HJ, de Graaf-Hess A, Blom HJ, Monnens LA, van den Heuvel LP, Levtchenko EN (2007) Cystine dimethylester model of cystinosis: still reliable? Pediatr Res 62:151–155

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by grants from Conselho Nacional de Desenvolvimento Científico e tecnológico (CNPq-Brazil), Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS, RS-Brazil), Programa de Núcleos de Excelência (PRONEX-CNPq /FAPERGS -Brazil) and Rede instituto Brasileiro de Neurociências (FINEP /IBN-Net #01.06.0842-00)

Author information

Authors and Affiliations

  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600, CEP 90.035-003, Porto Alegre, RS, Brazil

    Vandré Casagrande Figueiredo, Luciane Rosa Feksa & Clovis Milton Duval Wannmacher

Authors
  1. Vandré Casagrande Figueiredo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luciane Rosa Feksa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Clovis Milton Duval Wannmacher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Clovis Milton Duval Wannmacher.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Figueiredo, V.C., Feksa, L.R. & Wannmacher, C.M.D. Cysteamine prevents inhibition of adenylate kinase caused by cystine in rat brain cortex. Metab Brain Dis 24, 373–381 (2009). https://doi.org/10.1007/s11011-009-9142-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-009-9142-9

Keywords

Search

Navigation