Skip to main content
Erschienen in: Diabetologia 8/2003

01.08.2003 | Article

Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension

verfasst von: Dr. F. Palm, J. Cederberg, P. Hansell, P. Liss, P.-O. Carlsson

Erschienen in: Diabetologia | Ausgabe 8/2003

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

Augmented formation of reactive oxygen species (ROS) induced by hyperglycaemia has been suggested to contribute to the development of diabetic nephropathy. This study was designed to evaluate the influence of streptozotocin (STZ)-induced diabetes mellitus, as well as the effects of preventing excessive ROS formation by α-tocopherol treatment, on regional renal blood flow, oxygen tension and oxygen consumption in anaesthetized Wistar Furth rats.

Methods

Non-diabetic and STZ-diabetic rats were investigated after 4 weeks with or without dietary treatment with the radical scavenger DL-α-tocopherol (vitamin E, 5%). A laser-Doppler technique was used to measure regional renal blood flow, whilst oxygen tension and consumption were measured using Clark-type microelectrodes.

Results

Renal oxygen tension, but not renal blood flow, was lower throughout the renal parenchyma of diabetic rats when compared to non-diabetic control rats. The decrease in oxygen tension was most pronounced in the renal medulla. Renal cellular oxygen consumption was markedly increased in diabetic rats, predominantly in the medullary region. Diabetes increased lipid peroxidation and protein carbonylation in the renal medulla. Treatment with α-tocopherol throughout the course of diabetes prevented diabetes-induced disturbances in oxidative stress, oxygen tension and consumption. The diabetic animals had a renal hypertrophy and a glomerular hyperfiltration, which were unaffected by α-tocopherol treatment.

Conclusions/interpretation

We conclude that oxidative stress occurs in kidneys of diabetic rats predominantly in the medullary region and relates to augmented oxygen consumption and impaired oxygen tension in the tissue.
Literatur
1.
Zurück zum Zitat King GL, Brownlee M (1996) The cellular and molecular mechanisms of diabetic complications. Endocrinol Metab Clin North Am 25:255–270PubMed King GL, Brownlee M (1996) The cellular and molecular mechanisms of diabetic complications. Endocrinol Metab Clin North Am 25:255–270PubMed
2.
Zurück zum Zitat Group TDCaCTR (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986PubMed Group TDCaCTR (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986PubMed
3.
Zurück zum Zitat Nishikawa T, Edelstein D, Du XL et al. (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790PubMed Nishikawa T, Edelstein D, Du XL et al. (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790PubMed
4.
Zurück zum Zitat Baynes JW (1991) Role of oxidative stress in development of complications in diabetes. Diabetes 40:405–412PubMed Baynes JW (1991) Role of oxidative stress in development of complications in diabetes. Diabetes 40:405–412PubMed
5.
Zurück zum Zitat Baynes JW, Thorpe SR (1999) Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48:1–9PubMed Baynes JW, Thorpe SR (1999) Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48:1–9PubMed
7.
Zurück zum Zitat Ceriello A, Morocutti A, Mercuri F et al. (2000) Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy. Diabetes 49:2170–2177PubMed Ceriello A, Morocutti A, Mercuri F et al. (2000) Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy. Diabetes 49:2170–2177PubMed
8.
Zurück zum Zitat Wolff SP (1993) Diabetes mellitus and free radicals. Free radicals, transition metals and oxidative stress in the aetiology of diabetes mellitus and complications. Br Med Bull 49:642–652PubMed Wolff SP (1993) Diabetes mellitus and free radicals. Free radicals, transition metals and oxidative stress in the aetiology of diabetes mellitus and complications. Br Med Bull 49:642–652PubMed
9.
Zurück zum Zitat Cameron NE, Cotter MA (1999) Effects of antioxidants on nerve and vascular dysfunction in experimental diabetes. Diabetes Res Clin Pract 45:137–146CrossRefPubMed Cameron NE, Cotter MA (1999) Effects of antioxidants on nerve and vascular dysfunction in experimental diabetes. Diabetes Res Clin Pract 45:137–146CrossRefPubMed
10.
Zurück zum Zitat Miyata T, Inagi R, Asahi K et al. (1998) Generation of protein carbonyls by glycoxidation and lipoxidation reactions with autoxidation products of ascorbic acid and polyunsaturated fatty acids. FEBS Lett 437:24–28CrossRefPubMed Miyata T, Inagi R, Asahi K et al. (1998) Generation of protein carbonyls by glycoxidation and lipoxidation reactions with autoxidation products of ascorbic acid and polyunsaturated fatty acids. FEBS Lett 437:24–28CrossRefPubMed
11.
Zurück zum Zitat Schnackenberg CG (2002) Physiological and pathophysiological roles of oxygen radicals in the renal microvasculature. Am J Physiol Regul Integr Comp Physiol 282:R335–R342PubMed Schnackenberg CG (2002) Physiological and pathophysiological roles of oxygen radicals in the renal microvasculature. Am J Physiol Regul Integr Comp Physiol 282:R335–R342PubMed
12.
Zurück zum Zitat Hansell P (1992) Evaluation of methods for estimating renal medullary blood flow. Ren Physiol Biochem 15:217–230PubMed Hansell P (1992) Evaluation of methods for estimating renal medullary blood flow. Ren Physiol Biochem 15:217–230PubMed
13.
Zurück zum Zitat Sadowski J, Kompanowska-Jezierska E, Dobrowolski L, Walkowska A, Badzynska B (1997) Simultaneous recording of tissue ion content and blood flow in rat renal medulla: evidence on interdependence. Am J Physiol 273:F658–F662PubMed Sadowski J, Kompanowska-Jezierska E, Dobrowolski L, Walkowska A, Badzynska B (1997) Simultaneous recording of tissue ion content and blood flow in rat renal medulla: evidence on interdependence. Am J Physiol 273:F658–F662PubMed
14.
Zurück zum Zitat Leichtweiss HP, Lubbers DW, Weiss C, Baumgartl H, Reschke W (1969) The oxygen supply of the rat kidney: measurements of intrarenal pO2. Pflugers Arch 309:328–349PubMed Leichtweiss HP, Lubbers DW, Weiss C, Baumgartl H, Reschke W (1969) The oxygen supply of the rat kidney: measurements of intrarenal pO2. Pflugers Arch 309:328–349PubMed
15.
Zurück zum Zitat Brezis M, Heyman SN, Epstein F (1994) Determinants of intrarenal oxygenation II. Hemodynamic effects. Am J Physiol 267:F1063–F1068PubMed Brezis M, Heyman SN, Epstein F (1994) Determinants of intrarenal oxygenation II. Hemodynamic effects. Am J Physiol 267:F1063–F1068PubMed
16.
Zurück zum Zitat Baines A, Ho P (2002) Glucose stimulates O2 consumption, NOS, and Na/H exchange in diabetic rat proximal tubules. Am J Physiol Renal Physiol 283:F286–F293PubMed Baines A, Ho P (2002) Glucose stimulates O2 consumption, NOS, and Na/H exchange in diabetic rat proximal tubules. Am J Physiol Renal Physiol 283:F286–F293PubMed
17.
Zurück zum Zitat Korner A, Eklof AC, Celsi G, Aperia A (1994) Increased renal metabolism in diabetes. Mechanism and functional implications. Diabetes 43:629–633PubMed Korner A, Eklof AC, Celsi G, Aperia A (1994) Increased renal metabolism in diabetes. Mechanism and functional implications. Diabetes 43:629–633PubMed
18.
Zurück zum Zitat Liss P, Nygren A, Revsbech NP, Ulfendahl H (1997) Intrarenal oxygen tension measured by a modified Clark electrode at normal and low blood pressure and after injection of x-ray contrast media. Pflugers Arch 434:705–711CrossRefPubMed Liss P, Nygren A, Revsbech NP, Ulfendahl H (1997) Intrarenal oxygen tension measured by a modified Clark electrode at normal and low blood pressure and after injection of x-ray contrast media. Pflugers Arch 434:705–711CrossRefPubMed
19.
Zurück zum Zitat Koivisto A, Pittner J, Froelich M, Persson AE (1999) Oxygen-dependent inhibition of respiration in isolated renal tubules by nitric oxide. Kidney Int 55:2368–2375CrossRefPubMed Koivisto A, Pittner J, Froelich M, Persson AE (1999) Oxygen-dependent inhibition of respiration in isolated renal tubules by nitric oxide. Kidney Int 55:2368–2375CrossRefPubMed
20.
Zurück zum Zitat Siman CM, Eriksson UJ (1997) Vitamin E decreases the occurrence of malformations in the offspring of diabetic rats. Diabetes 46:1054–1061PubMed Siman CM, Eriksson UJ (1997) Vitamin E decreases the occurrence of malformations in the offspring of diabetic rats. Diabetes 46:1054–1061PubMed
21.
Zurück zum Zitat Cederberg J, Siman CM, Eriksson UJ (2001) Combined treatment with vitamin E and vitamin C decreases oxidative stress and improves fetal outcome in experimental diabetic pregnancy. Pediatr Res 49:755–762PubMed Cederberg J, Siman CM, Eriksson UJ (2001) Combined treatment with vitamin E and vitamin C decreases oxidative stress and improves fetal outcome in experimental diabetic pregnancy. Pediatr Res 49:755–762PubMed
22.
Zurück zum Zitat Cameron NE, Cotter MA (1997) Metabolic and vascular factors in the pathogenesis of diabetic neuropathy. Diabetes 46 [Suppl 2]:S31–S37 Cameron NE, Cotter MA (1997) Metabolic and vascular factors in the pathogenesis of diabetic neuropathy. Diabetes 46 [Suppl 2]:S31–S37
23.
Zurück zum Zitat Linsenmeier RA, Braun RD, McRipley MA et al. (1998) Retinal hypoxia in long-term diabetic cats. Invest Ophthalmol Vis Sci 39:1647–1657PubMed Linsenmeier RA, Braun RD, McRipley MA et al. (1998) Retinal hypoxia in long-term diabetic cats. Invest Ophthalmol Vis Sci 39:1647–1657PubMed
24.
Zurück zum Zitat Melin J, Hellberg O, Akyurek LM, Kallskog O, Larsson E, Fellstrom BC (1997) Ischemia causes rapidly progressive nephropathy in the diabetic rat. Kidney Int 52:985–991PubMed Melin J, Hellberg O, Akyurek LM, Kallskog O, Larsson E, Fellstrom BC (1997) Ischemia causes rapidly progressive nephropathy in the diabetic rat. Kidney Int 52:985–991PubMed
25.
Zurück zum Zitat Brezis M, Rosen S (1995) Hypoxia of the renal medulla—its implication for disease. New Engl J Med 332:647–655CrossRefPubMed Brezis M, Rosen S (1995) Hypoxia of the renal medulla—its implication for disease. New Engl J Med 332:647–655CrossRefPubMed
26.
Zurück zum Zitat Zhong Z, Arteel GE, Connor HD et al. (1998) Cyclosporin A increases hypoxia and free radical production in rat kidneys: prevention by dietary glycine. Am J Physiol 275:F595–F604PubMed Zhong Z, Arteel GE, Connor HD et al. (1998) Cyclosporin A increases hypoxia and free radical production in rat kidneys: prevention by dietary glycine. Am J Physiol 275:F595–F604PubMed
27.
Zurück zum Zitat Brezis M, Rosen S, Silva P, Epstein FH (1984) Renal ischemia: a new perspective. Kidney Int 26:375–383PubMed Brezis M, Rosen S, Silva P, Epstein FH (1984) Renal ischemia: a new perspective. Kidney Int 26:375–383PubMed
28.
Zurück zum Zitat Fine LG, Orphanides C, Norman JT (1998) Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int [Suppl 65]:S74–S78 Fine LG, Orphanides C, Norman JT (1998) Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int [Suppl 65]:S74–S78
29.
Zurück zum Zitat Fine LG, Bandyopadhay D, Norman JT (2000) Is there a common mechanism for the progression of different types of renal diseases other than proteinuria? Towards the unifying theme of chronic hypoxia. Kidney Int [Suppl 75]:S22–S26 Fine LG, Bandyopadhay D, Norman JT (2000) Is there a common mechanism for the progression of different types of renal diseases other than proteinuria? Towards the unifying theme of chronic hypoxia. Kidney Int [Suppl 75]:S22–S26
30.
Zurück zum Zitat Sahai A, Mei C, Schrier RW, Tannen RL (1999) Mechanisms of chronic hypoxia-induced renal cell growth. Kidney Int 56:1277–1281CrossRefPubMed Sahai A, Mei C, Schrier RW, Tannen RL (1999) Mechanisms of chronic hypoxia-induced renal cell growth. Kidney Int 56:1277–1281CrossRefPubMed
31.
Zurück zum Zitat Orphanides C, Fine LG, Norman JT (1997) Hypoxia stimulates proximal tubular cell matrix production via a TGF-beta1-independent mechanism. Kidney Int 52:637–647PubMed Orphanides C, Fine LG, Norman JT (1997) Hypoxia stimulates proximal tubular cell matrix production via a TGF-beta1-independent mechanism. Kidney Int 52:637–647PubMed
32.
Zurück zum Zitat Sodhi CP, Phadke SA, Batlle D, Sahai A (2001) Hypoxia and high glucose cause exaggerated mesangial cell growth and collagen synthesis: role of osteopontin. Am J Physiol Renal Physiol 280:F667–F674PubMed Sodhi CP, Phadke SA, Batlle D, Sahai A (2001) Hypoxia and high glucose cause exaggerated mesangial cell growth and collagen synthesis: role of osteopontin. Am J Physiol Renal Physiol 280:F667–F674PubMed
33.
Zurück zum Zitat MacManus MP, Maxwell AP, Abram WP, Bridges JM (1989) The effect of hypobaric hypoxia on misonidazole binding in normal and tumour-bearing mice. Br J Cancer 59:349–352PubMed MacManus MP, Maxwell AP, Abram WP, Bridges JM (1989) The effect of hypobaric hypoxia on misonidazole binding in normal and tumour-bearing mice. Br J Cancer 59:349–352PubMed
34.
Zurück zum Zitat Ling LL, Sutherland RM (1986) Modulation of the hypoxic toxicity and binding of misonidazole by glucose. Br J Cancer 54:911–917PubMed Ling LL, Sutherland RM (1986) Modulation of the hypoxic toxicity and binding of misonidazole by glucose. Br J Cancer 54:911–917PubMed
35.
Zurück zum Zitat Goligorsky MS, Chen J, Brodsky S (2001) Workshop: endothelial cell dysfunction leading to diabetic nephropathy : focus on nitric oxide. Hypertension 37:744–748PubMed Goligorsky MS, Chen J, Brodsky S (2001) Workshop: endothelial cell dysfunction leading to diabetic nephropathy : focus on nitric oxide. Hypertension 37:744–748PubMed
36.
Zurück zum Zitat Vaziri ND, Ni Z, Oveisi F, Liang K, Pandian R (2002) Enhanced nitric oxide inactivation and protein nitration by reactive oxygen species in renal insufficiency. Hypertension 39:135–141CrossRefPubMed Vaziri ND, Ni Z, Oveisi F, Liang K, Pandian R (2002) Enhanced nitric oxide inactivation and protein nitration by reactive oxygen species in renal insufficiency. Hypertension 39:135–141CrossRefPubMed
37.
Zurück zum Zitat Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95PubMed Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95PubMed
38.
Zurück zum Zitat Clementi E, Brown GC, Foxwell N, Moncada S (1999) On the mechanism by which vascular endothelial cells regulate their oxygen consumption. Proc Natl Acad Sci USA 96:1559–1562PubMed Clementi E, Brown GC, Foxwell N, Moncada S (1999) On the mechanism by which vascular endothelial cells regulate their oxygen consumption. Proc Natl Acad Sci USA 96:1559–1562PubMed
39.
Zurück zum Zitat Brodsky SV, Gao S, Li H, Goligorsky MS (2002) Hyperglycemic switch from mitochondrial nitric oxide to superoxide production in endothelial cells. Am J Physiol Heart Circ Physiol 283:H2130–H2139PubMed Brodsky SV, Gao S, Li H, Goligorsky MS (2002) Hyperglycemic switch from mitochondrial nitric oxide to superoxide production in endothelial cells. Am J Physiol Heart Circ Physiol 283:H2130–H2139PubMed
40.
Zurück zum Zitat Smith OK, Long CN (1971) Renal gluconeogenesis in eviscerated diabetic rats. Proc Natl Acad Sci USA 68:1618–1622PubMed Smith OK, Long CN (1971) Renal gluconeogenesis in eviscerated diabetic rats. Proc Natl Acad Sci USA 68:1618–1622PubMed
41.
Zurück zum Zitat Peroni O, Large V, Diraison F, Beylot M (1997) Glucose production and gluconeogenesis in postabsorptive and starved normal and streptozotocin-diabetic rats. Metabolism 46:1358–1363PubMed Peroni O, Large V, Diraison F, Beylot M (1997) Glucose production and gluconeogenesis in postabsorptive and starved normal and streptozotocin-diabetic rats. Metabolism 46:1358–1363PubMed
42.
Zurück zum Zitat Horstman P (1951) The oxygen consumption in diabetes mellitus. Acta Med Scand 139:326–330 Horstman P (1951) The oxygen consumption in diabetes mellitus. Acta Med Scand 139:326–330
43.
Zurück zum Zitat Kinalski M, Sledziewski A, Telejko B et al. (2000) Lipid peroxidation and scavenging enzyme activity in streptozotocin-induced diabetes. Acta Diabetol 37:179–183CrossRefPubMed Kinalski M, Sledziewski A, Telejko B et al. (2000) Lipid peroxidation and scavenging enzyme activity in streptozotocin-induced diabetes. Acta Diabetol 37:179–183CrossRefPubMed
44.
Zurück zum Zitat Sun F, Iwaguchi K, Shudo R, Nagaki Y, Tanaka K, Ikeda K, Tokumaru S, Kojo S (1999) Change in tissue concentrations of lipid hydroperoxides, vitamin C and vitamin E in rats with streptozotocin-induced diabetes. Clin Sci (Lond) 96:185–190 Sun F, Iwaguchi K, Shudo R, Nagaki Y, Tanaka K, Ikeda K, Tokumaru S, Kojo S (1999) Change in tissue concentrations of lipid hydroperoxides, vitamin C and vitamin E in rats with streptozotocin-induced diabetes. Clin Sci (Lond) 96:185–190
45.
Zurück zum Zitat Elangovan V, Shohami E, Gati I, Kohen R (2000) Increased hepatic lipid soluble antioxidant capacity as compared to other organs of streptozotocin-induced diabetic rats: a cyclic voltammetry study. Free Radic Res 32:125–134PubMed Elangovan V, Shohami E, Gati I, Kohen R (2000) Increased hepatic lipid soluble antioxidant capacity as compared to other organs of streptozotocin-induced diabetic rats: a cyclic voltammetry study. Free Radic Res 32:125–134PubMed
46.
Zurück zum Zitat Cederberg J, Basu S, Eriksson UJ (2001) Increased rate of lipid peroxidation and protein carbonylation in experimental diabetic pregnancy. Diabetologia 44:766–774CrossRefPubMed Cederberg J, Basu S, Eriksson UJ (2001) Increased rate of lipid peroxidation and protein carbonylation in experimental diabetic pregnancy. Diabetologia 44:766–774CrossRefPubMed
47.
Zurück zum Zitat Odetti P, Garibaldi S, Noberasco G, Aragno I, Valentini S, Traverso N, Marinari UM (1999) Levels of carbonyl groups in plasma proteins of type 2 diabetes mellitus subjects. Acta Diabetol 36:179–183CrossRefPubMed Odetti P, Garibaldi S, Noberasco G, Aragno I, Valentini S, Traverso N, Marinari UM (1999) Levels of carbonyl groups in plasma proteins of type 2 diabetes mellitus subjects. Acta Diabetol 36:179–183CrossRefPubMed
48.
Zurück zum Zitat Koya D, Lee IK, Ishii H, Kanoh H, King GL (1997) Prevention of glomerular dysfunction in diabetic rats by treatment with d-alpha-tocopherol. J Am Soc Nephrol 8:426–435PubMed Koya D, Lee IK, Ishii H, Kanoh H, King GL (1997) Prevention of glomerular dysfunction in diabetic rats by treatment with d-alpha-tocopherol. J Am Soc Nephrol 8:426–435PubMed
49.
Zurück zum Zitat Craven PA, DeRubertis FR, Kagan VE, Melhem M, Studer RK (1997) Effects of supplementation with vitamin C or E on albuminuria, glomerular TGF-beta, and glomerular size in diabetes. J Am Soc Nephrol 8:1405–1414PubMed Craven PA, DeRubertis FR, Kagan VE, Melhem M, Studer RK (1997) Effects of supplementation with vitamin C or E on albuminuria, glomerular TGF-beta, and glomerular size in diabetes. J Am Soc Nephrol 8:1405–1414PubMed
50.
Zurück zum Zitat Kim SS, Gallaher DD, Csallany AS (2000) Vitamin E and probucol reduce urinary lipophilic aldehydes and renal enlargement in streptozotocin-induced diabetic rats. Lipids 35:1225–1237PubMed Kim SS, Gallaher DD, Csallany AS (2000) Vitamin E and probucol reduce urinary lipophilic aldehydes and renal enlargement in streptozotocin-induced diabetic rats. Lipids 35:1225–1237PubMed
Metadaten
Titel
Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension
verfasst von
Dr. F. Palm
J. Cederberg
P. Hansell
P. Liss
P.-O. Carlsson
Publikationsdatum
01.08.2003
Verlag
Springer-Verlag
Erschienen in
Diabetologia / Ausgabe 8/2003
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-003-1155-z

Weitere Artikel der Ausgabe 8/2003

Diabetologia 8/2003 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

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.

Strenge Blutdruckeinstellung lohnt auch im Alter noch

30.04.2024 Arterielle Hypertonie Nachrichten

Ältere Frauen, die von chronischen Erkrankungen weitgehend verschont sind, haben offenbar die besten Chancen, ihren 90. Geburtstag zu erleben, wenn ihr systolischer Blutdruck < 130 mmHg liegt. Das scheint selbst für 80-Jährige noch zu gelten.

Sind Frauen die fähigeren Ärzte?

30.04.2024 Gendermedizin Nachrichten

Patienten, die von Ärztinnen behandelt werden, dürfen offenbar auf bessere Therapieergebnisse hoffen als Patienten von Ärzten. Besonders gilt das offenbar für weibliche Kranke, wie eine Studie zeigt.

Update Innere Medizin

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