nach oben

Diabetologia

Erschienen in:

01.05.2012 | Article

Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes

verfasst von: M. Friederich Persson, S. Franzén, S.-B. Catrina, G. Dallner, P. Hansell, K. Brismar, F. Palm

Erschienen in: Diabetologia | Ausgabe 5/2012

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes.

Methods

Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment.

Results

Untreated db/db mice displayed mitochondrial uncoupling, manifested as glutamate-stimulated oxygen consumption (2.7 ± 0.1 vs 0.2 ± 0.1 pmol O₂ s⁻¹ [mg protein]⁻¹), glomerular hyperfiltration (502 ± 26 vs 385 ± 3 μl/min), increased proteinuria (21 ± 2 vs 14 ± 1, μg/24 h), mitochondrial fragmentation (fragmentation score 2.4 ± 0.3 vs 0.7 ± 0.1) and size (1.6 ± 0.1 vs 1 ± 0.0 μm) compared with untreated controls. All alterations were prevented or reduced by CoQ10 treatment. Mitochondrial uncoupling was partly inhibited by the UCP inhibitor GDP (−1.1 ± 0.1 pmol O₂ s⁻¹ [mg protein]⁻¹). UCP-2 protein levels were similar in untreated control and db/db mice (67 ± 9 vs 67 ± 4 optical density; OD) but were reduced in CoQ10 treated groups (43 ± 2 and 38 ± 7 OD).

Conclusions/interpretation

db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress.

Thomas MC, Weekes AJ, Broadley OJ, Cooper ME, Mathew TH (2006) The burden of chronic kidney disease in Australian patients with type 2 diabetes (the NEFRON study). Med J Aust 185:140–144PubMed

Mokdad AH, Ford ES, Bowman BA et al (2000) Diabetes trends in the U.S.: 1990–1998. Diabetes Care 23:1278–1283PubMedCrossRef

Wild S, Roglic G, Green A, Sicree R, King H (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053PubMedCrossRef

Harvey JN (2003) Trends in the prevalence of diabetic nephropathy in type 1 and type 2 diabetes. Curr Opin Nephrol Hypertens 12:317–322PubMedCrossRef

Steffes MW, Bilous RW, Sutherland DE, Mauer SM (1992) Cell and matrix components of the glomerular mesangium in type I diabetes. Diabetes 41:679–684PubMedCrossRef

Mauer SM, Steffes MW, Ellis EN, Sutherland DE, Brown DM, Goetz FC (1984) Structural–functional relationships in diabetic nephropathy. J Clin Invest 74:1143–1155PubMedCrossRef

Mauer M, Drummond K (2002) The early natural history of nephropathy in type 1 diabetes: I. Study design and baseline characteristics of the study participants. Diabetes 51:1572–1579PubMedCrossRef

Vallon V (2011) The proximal tubule in the pathophysiology of the diabetic kidney. Am J Physiol Regul Integr Comp Physiol 300:R1009–R1022PubMedCrossRef

Palm F, Cederberg J, Hansell P, Liss P, Carlsson PO (2003) Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension. Diabetologia 46:1153–1160PubMedCrossRef

10.

Nishikawa T, Edelstein D, Du XL et al (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790PubMedCrossRef

11.

St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277:44784–44790PubMedCrossRef

12.

Yu T, Robotham JL, Yoon Y (2006) Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci USA 103:2653–2658PubMedCrossRef

13.

Miwa S, Brand MD (2003) Mitochondrial matrix reactive oxygen species production is very sensitive to mild uncoupling. Biochem Soc Trans 31:1300–1301PubMedCrossRef

14.

Echtay KS, Esteves TC, Pakay JL et al (2003) A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. EMBO J 22:4103–4110PubMedCrossRef

15.

Fleury C, Neverova M, Collins S et al (1997) Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet 15:269–272PubMedCrossRef

16.

Friederich M, Nordquist L, Olerud J, Johansson M, Hansell P, Palm F (2009) Identification and distribution of uncoupling protein isoforms in the normal and diabetic kidney. Adv Exp Med Biol 645:205–212PubMedCrossRef

17.

Alan L, Smolkova K, Kronusova E, Santorova J, Jezek P (2009) Absolute levels of transcripts for mitochondrial uncoupling proteins UCP2, UCP3, UCP4, and UCP5 show different patterns in rat and mice tissues. J Bioenerg Biomembr 41:71–78PubMedCrossRef

18.

Friederich M, Fasching A, Hansell P, Nordquist L, Palm F (2008) Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells. Biochim Biophys Acta 1777:935–940PubMedCrossRef

19.

Rosenberger C, Khamaisi M, Abassi Z et al (2008) Adaptation to hypoxia in the diabetic rat kidney. Kidney Int 73:34–42PubMedCrossRef

20.

Echtay KS, Murphy MP, Smith RA, Talbot DA, Brand MD (2002) Superoxide activates mitochondrial uncoupling protein 2 from the matrix side. Studies using targeted antioxidants. J Biol Chem 277:47129–47135PubMedCrossRef

21.

Munusamy S, MacMillan-Crow LA (2009) Mitochondrial superoxide plays a crucial role in the development of mitochondrial dysfunction during high glucose exposure in rat renal proximal tubular cells. Free Radic Biol Med 46:1149–1157PubMedCrossRef

22.

Crane FL, Hatefi Y, Lester RL, Widmer C (1957) Isolation of a quinone from beef heart mitochondria. Biochim Biophys Acta 25:220–221PubMedCrossRef

23.

Sun IL, Sun EE, Crane FL, Morre DJ, Lindgren A, Low H (1992) Requirement for coenzyme Q in plasma membrane electron transport. Proc Natl Acad Sci USA 89:11126–11130PubMedCrossRef

24.

Fontaine E, Bernardi P (1999) Progress on the mitochondrial permeability transition pore: regulation by complex I and ubiquinone analogs. J Bioenerg Biomembr 31:335–345PubMedCrossRef

25.

Frei B, Kim MC, Ames BN (1990) Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc Natl Acad Sci USA 87:4879–4883PubMedCrossRef

26.

Echtay KS, Winkler E, Frischmuth K, Klingenberg M (2001) Uncoupling proteins 2 and 3 are highly active H(+) transporters and highly nucleotide sensitive when activated by coenzyme Q (ubiquinone). Proc Natl Acad Sci USA 98:1416–1421PubMedCrossRef

27.

Lee SM, Bressler R (1981) Prevention of diabetic nephropathy by diet control in the db/db mouse. Diabetes 30:106–111PubMedCrossRef

28.

Cohen MP, Clements RS, Hud E, Cohen JA, Ziyadeh FN (1996) Evolution of renal function abnormalities in the db/db mouse that parallels the development of human diabetic nephropathy. Exp Nephrol 4:166–171PubMed

29.

Stridh S, Sallstrom J, Friden M, Hansell P, Nordquist L, Palm F (2009) C-peptide normalizes glomerular filtration rate in hyperfiltrating conscious diabetic rats. Adv Exp Med Biol 645:219–225PubMedCrossRef

30.

Gabrielsson J, Weiner P (2006) Non-compartmental analysis. In: Pharmacokinetic and pharmacodynamic data analysis: concepts and applications. Swedish Pharmaceutical Press, Stockholm

31.

Kobayashi K, Forte TM, Taniguchi S, Ishida BY, Oka K, Chan L (2000) The db/db mouse, a model for diabetic dyslipidemia: molecular characterization and effects of Western diet feeding. Metabolism 49:22–31PubMedCrossRef

32.

How OJ, Aasum E, Severson DL, Chan WY, Essop MF, Larsen TS (2006) Increased myocardial oxygen consumption reduces cardiac efficiency in diabetic mice. Diabetes 55:466–473PubMedCrossRef

33.

Echtay KS, Roussel D, St-Pierre J et al (2002) Superoxide activates mitochondrial uncoupling proteins. Nature 415:96–99PubMedCrossRef

34.

Couplan E, del Mar Gonzalez-Barroso M, Alves-Guerra MC, Ricquier D, Goubern M, Bouillaud F (2002) No evidence for a basal, retinoic, or superoxide-induced uncoupling activity of the uncoupling protein 2 present in spleen or lung mitochondria. J Biol Chem 277:26268–26275PubMedCrossRef

35.

Krauss S, Zhang CY, Scorrano L et al (2003) Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction. J Clin Invest 112:1831–1842PubMed

36.

Hurtaud C, Gelly C, Chen Z, Levi-Meyrueis C, Bouillaud F (2007) Glutamine stimulates translation of uncoupling protein 2mRNA. Cell Mol Life Sci 64:1853–1860PubMedCrossRef

37.

Kaneda K, Iwao J, Sakata N, Takebayashi S (1992) Correlation between mitochondrial enlargement in renal proximal tubules and microalbuminuria in rats with early streptozotocin-induced diabetes. Acta Pathol Jpn 42:855–860PubMed

38.

Asaba K, Tojo A, Onozato ML et al (2005) Effects of NADPH oxidase inhibitor in diabetic nephropathy. Kidney Int 67:1890–1898PubMedCrossRef

39.

Lonn E, Yusuf S, Hoogwerf B et al (2002) Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy. Diabetes Care 25:1919–1927PubMedCrossRef

40.

Alkhalaf A, Klooster A, van Oeveren W et al (2010) A double-blind, randomized, placebo-controlled clinical trial on benfotiamine treatment in patients with diabetic nephropathy. Diabetes Care 33:1598–1601PubMedCrossRef

41.

Haidara MA, Mikhailidis DP, Rateb MA et al (2009) Evaluation of the effect of oxidative stress and vitamin E supplementation on renal function in rats with streptozotocin-induced type 1 diabetes. J Diabetes Complications 23:130–136PubMedCrossRef

42.

Mogensen CE (1984) Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 310:356–360PubMedCrossRef

43.

O'Donnell MP, Kasiske BL, Keane WF (1988) Glomerular hemodynamic and structural alterations in experimental diabetes mellitus. FASEB J 2:2339–2347PubMed

44.

Rudberg S, Persson B, Dahlquist G (1992) Increased glomerular filtration rate as a predictor of diabetic nephropathy—an 8-year prospective study. Kidney Int 41:822–828PubMedCrossRef

45.

Ghosh S, Khazaei M, Moien-Afshari F et al (2009) Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice. Am J Physiol Renal Physiol 296:F700–F708PubMedCrossRef

46.

Peixoto EB, Pessoa BS, Biswas SK, Lopes de Faria JB (2009) Antioxidant SOD mimetic prevents NADPH oxidase-induced oxidative stress and renal damage in the early stage of experimental diabetes and hypertension. Am J Nephrol 29:309–318PubMedCrossRef

47.

Fujita H, Fujishima H, Chida S et al (2009) Reduction of renal superoxide dismutase in progressive diabetic nephropathy. J Am Soc Nephrol 20:1303–1313PubMedCrossRef

48.

Nangaku M (2006) Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol 17:17–25PubMedCrossRef

49.

McCullough PA, Adam A, Becker CR et al (2006) Risk prediction of contrast-induced nephropathy. Am J Cardiol 98:27K–36KPubMedCrossRef

50.

House AA, Silva Oliveira S, Ronco C (2007) Anti-inflammatory drugs and the kidney. Int J Artif Organs 30:1042–1046PubMed

Titel: Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes
verfasst von: M. Friederich Persson
S. Franzén
S.-B. Catrina
G. Dallner
P. Hansell
K. Brismar
F. Palm
Publikationsdatum: 01.05.2012
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 5/2012
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-012-2469-5

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Echinokokkose medikamentös behandeln oder operieren?

06.05.2024 DCK 2024 Kongressbericht

Die Therapie von Echinokokkosen sollte immer in spezialisierten Zentren erfolgen. Eine symptomlose Echinokokkose kann – egal ob von Hunde- oder Fuchsbandwurm ausgelöst – konservativ erfolgen. Wenn eine Op. nötig ist, kann es sinnvoll sein, vorher Zysten zu leeren und zu desinfizieren.

Umsetzung der POMGAT-Leitlinie läuft

03.05.2024 DCK 2024 Kongressbericht

Seit November 2023 gibt es evidenzbasierte Empfehlungen zum perioperativen Management bei gastrointestinalen Tumoren (POMGAT) auf S3-Niveau. Vieles wird schon entsprechend der Empfehlungen durchgeführt. Wo es im Alltag noch hapert, zeigt eine Umfrage in einem Klinikverbund.

Proximale Humerusfraktur: Auch 100-Jährige operieren?

01.05.2024 DCK 2024 Kongressbericht

Mit dem demographischen Wandel versorgt auch die Chirurgie immer mehr betagte Menschen. Von Entwicklungen wie Fast-Track können auch ältere Menschen profitieren und bei proximaler Humerusfraktur können selbst manche 100-Jährige noch sicher operiert werden.

Die „Zehn Gebote“ des Endokarditis-Managements

30.04.2024 Endokarditis Leitlinie kompakt

Worauf kommt es beim Management von Personen mit infektiöser Endokarditis an? Eine Kardiologin und ein Kardiologe fassen die zehn wichtigsten Punkte der neuen ESC-Leitlinie zusammen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 5/2012

Ectopic expression of glucagon receptor in skeletal muscles improves glucose homeostasis in a mouse model of diabetes

The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes

Glycaemic control is improved by 7 days of aerobic exercise training in patients with type 2 diabetes

Exercise in type 2 diabetes: to resist or to endure?

Impact of diabetes and glycaemic control on peripheral artery disease in Japanese patients with end-stage renal disease: long-term follow-up study from the beginning of haemodialysis