Microsoft Word Dissertation-Ute-Daig-05. 09. 05. doc

 
89
35 Peters H, Border WA, Noble NA: L-arginine supplementation increases 
mesangial cell injury and subsequent tissue fibrosis in experimental 
glomerulonephritis. Kid Int. 1999, 
55
, S.2264-273,  
36 Peters H, Noble NA: dietary L-arginine in renal disease. Sem Nephrol. 1996, 
16 No. 6
, S.567-575,  
37 Noris M, Remuzzi G: Physiology and Pathophysiology of nitric oxide in 
chronic renal disease. Proc Assoc Am Physicians. 1999, 
111
, S.602-610,  
38 Kone BC: Nitric oxide in renal health and disease. Am J Kid Dis. 1997, 
30
, 
S.311-333,  
41 Forstermann U, Closs EI, Pollock JS, nakane M, Schwar P, Gath I, Kleinert 
H: Nitric oxide synthase isozymes. Characterization, purification, 
molecular cloning and functions. Hypertension. 1994, 
23
, S.1121-1131,  
43 Trachtmann H, Futterweit S, Singhal P: Nitric oxide modulates the synthesis 
of extracellulär matrix proteins in cultured rat mesangial cells. Biochem 
Biophys Res Commun. 1995, 
207
, S.120-125,  
44 Trachtmann H, Futterweit S, Garg P, Reddy K, Singhal P: Nitric oxide 
stimulates the activity of a 72-kDa neutral matrix metalloproteinase in 
cultured rat mesangial cells. Biochem Biophys Res Commun. 1996, 
218
, 
S.704-708,  
45 Craven PA, Studer RK, Felder J, Phillips S, DeRubertis FR: Nitric oxide 
inhibition of transfoorming grwoth factor-beta and collagen sythesis in 
mesangial cells. Diabetes. 1997, 
46
, S.671-681,  
46 Shultz PJ, Schorer AE, Raij L: Effects of endothelium-derived relaxing factor 
and nitric oxide on rat mesangial cells. Am J Physiol. 1990, 
258
, S.F162-
F167,  
47 Hogan M, Cerami A, Bucala R: Advanced glycolisation endproducts block 
the antiproliferative effect of nitric oxide. Role in the vascular and renal 
complications of diabetes mellitus. J Clin Invest. 1992, 
90
, S.1110-1115,  
50 Bagchus WM, Hoedemaker PJ, Rozing J, Bakker WW: Glomerulonephritis 
induced by monoclonal Anti-thy-1.1antibodies. Lab Invest. 1986, 
55
, 
S.680-687,  

---

 
90
51 Narita I, Border WA, Ketteler M, Noble NA: Nitric oxide mediates 
immunologic injury to kidney mesangium in experimental 
glomerulonephritis. Lab Invest. 1995, 
72
, S.17-24,  
52 Schlondorff D, Nelson PJ, Luckow B, Banas B: Chemokines and renal 
disease. Kidney Int. 1997, 
51
, S.610-621,  
53 Floege J, Grone HJ: Progression of renal failure: What is the role of 
Zytokines. Nephrol Dial Transplant. 1995, 
10
, S.1575-1586,  
54 Peters H, Border WA, Noble NA: Tandem antifibrotic actions of L-arginine 
supplementation and low protein diet during the repair phase of 
experimental glomerulonephritis. Kidney Int. 2000, 
57
, S.922-1001,  
55 Rerolle JP, Hertig A, Nguyen G, Sraer JD, Rondeau EP: Plasminogen 
activator inhibitor type 1 is a potential target in renal fibrosis. Kidney Int. 
2000, 
58
, S.1841-1850,  
56 Tierschutzgesetz vom 02.09.1975. Band BGBI. 2002 S.2313-2610 Ref. 
Type: Patent,  
57 Tierschutzgesetz in der Fassung vom 17.02.1993. Band BGB1. 1993 S.254 
zuletzt geändert durch Artikel 86 des EWR-Ausführungsgesetzes vom 
27.04.1993 BGB II S. 512 Ref. Type: Patent,  
58 Feelisch M : The use of nitric oxide donors in pharmacological studies. 
Nauyn Schmiedebergs Arch Pharmacol. 1998, 
358
, S.113-122 ,  
59 Baylis C, Mitruka B, Deng A: Chronic blockade of nitric oxide synthesis in the 
rat produces systemic hypertension and glomerular damage. J Clin 
Invest. 1992, 
90
, S.278-281,  
61 van den Meiracker A, van der Linde N, Broere A, Derkx F, Boomsma F: 
Effects of L-Arginine and L-NAME on the renal function in hypertensive 
and normotensive subjects. Nephron. 2002, 
91
, S.444-451,  
62 Benigni A, Zoija C, Norris M et al: Renoprotection by nitric oxide donor and 
lisinopril in the remnant kidney model. Am J Kidney Dis. 1999, 
33
, S.746-
753,  

---

 
91
63 Rangan GK, Wang Y, Harris DC: Pharmacologic modulators of nitric oxide 
exacerbate tubulointerstitial inflammation in proteinuric rats. J Am Soc 
Nephrol. 2001, 
12
, S.1696-1705,  
64 Attia DM, Ni ZN, Boer P et al.: Proteinuria is preceeded by decreased nitric 
oxide synthesis and prevented by a NO donor in cholesterol-fed rats. 
Kidney Int. 2002, 
61
, S.1776-1787,  
65 Peters H, Noble NA, Border WA: Targeting TGF-beta overexpression in 
renal disease: Maximizing the antifibrotic action of angiotensin II 
blockade. Kidney Int. 1998, 
54
, S.1575-1583,  
66 Vodovotz Y, Kwon NS, Pospischil M, Manning J, Paik J, Nathan C: 
Inactivation of nitric oxide synthase after prolonged incubation of mouse 
macrophages with IFN-gamma and bacterial lipopolysaccharide, J 
Immunol. 1994, 
152
(8), S. 4110-8,  
67 Stuehr DJ, Cho HJ, Kwon NS, Weise MF, Nathan CF: Purification and 
characterization of the cytokine-induced macrophage nitric oxide 
synthase: an FAD- and FMN-containing flavoprotein. Proc Natl Acad Sci 
U S A. 1991, 
88
(17), S. 7773-7777,  
68 Rennard SI, Berg R, Martin GR, Foidart JM, Robey PG: Enzyme-linked 
immunoassay (ELISA) for connective tissue components. Anla Biochem. 
1980, 
104
, S.205-214,  
69 Schmidt RJ, Baylis C: Total nitric oxide production is low in patients with 
chronic renal disease. Kidney Int. 2000, 
58
, S.1261-1266,  
70 Reyes AA, Karl IE, Yates J, Klahr S: Low plasma and renal tissue levels in 
rats with obstructive nephropathy. Kidney Int. 1994, 
45
, S.782-787,  
71 Baylis C, Vallance P: Measurement of nitrite and nitrate levels in plasma and 
urine - What does this measure tell us about the activity of the 
enogenous nitric oxide system?. Curr Opin Nephrol Hypertens. 1998, 
7
, 
S.59-62,  
72 Chen PY, Sanders PW: L-arginine abrogates salt-sensitive hypertension in 
Dahl/Rapp rats. J Clin Invest. 1991, 
88
, S.1559-1567,  
73 Shihab FS, Yi H, Bennet WM, Andoh TF: Effect of nitric oxide modulation on 
TGF-beta1 and matrix proteins in chronic cyclosporine nephrotoxicity. 
Kidney Int. 2000, 
58
, S.1174-1185,  

---

 
92
74 Ribeiro MO, Antunes E, Muscara MN et al.: Nifedipine prevents renal injury 
in rats with chronic nitric oxide inhibition. Hypertens. 1995, 
26
, S.150-
155,  
75 Wenzel UO, Wolf F, Thaiss F et. al: Renovascular hypertension does not 
influence repair of glomerular lesions induced by anti-thymocyte 
glomerulonephritis. Kidney Int. 2000, 
58
, S.1135-1147,  
76 Vandenbossche GM, De Muyunck C, Colardyn F, Remon JP: Light stability 
of molsidominein infusion fluids. J Pharm Pharmacol. 1993, 
45
, S.486-
488,  
77 Mattson DL, Wu F: Nitric oxide synthase activity and isoforms in rat renal 
vasculatur. Hypertens. 2000, 
35
, S.337-341,  
78 Öztürk H, Aldemir M, Büyükbayram H et al.: The effects of the nitric oxide 
donor molsidomine prevent warm ischemia-reperfusion injury in the rat 
renal-A functional and histopathological study. Int Urol Nephrol. 2001, 
32
, 
S.601-607,  
79 Rangan GK, Wang Y, Harris DC: Pharmacological modulators of nitric oxide 
exacerbate tubuloinstertial inflammation in proteinuric rats. J Am Soc 
Nephrol. 2001, 
12
, S.1696-1705,  
80 Nori E, Peresleni T, Miller F, Goligorsky MS: In vivo targeting of inducible NO 
synthase with oligodesoxynucleotides protects rat kidney against 
ischemia. J Clin Invest. 1996, 
97
, S.1377-2383,  
81 Vos IH, Joles JA, Schurink M, et al.: Inhibition of inducible nitric oxide 
synthase improves graft function and reduces tubulointerstitial injury in 
renal allograft rejection. Eur J Pharmacol. 2000, 
391
, S.31-38,  
82 Noiri E, Peresleni T, Miller F, Goligorsky MS: The role of nitric oxide in the 
pathogenesis of spontaneus murine autoimmune disease: Increased 
nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr 
mice, and reduction of spontaneous glomerulonephritis and arthritis by 
orally administered NG-Monomethyl-L-Arginine. J Clin Invest. 1996, 
97
, 
S.2377-2383,  

---

 
93
83 Kashem A, Endoh M, Yano N, et al.: Expression of inducible-NOS in human 
glomerulonephritis. The possible source is infiltrating 
monocytes/macrophages. Kidney Int. 1996, 
50
, S.392-399,  
84 Peters H, Border WA, Rückert M et al.: L-Arginine supplementation 
accelerates renal fibrosis and shortens life span in experimental lupus 
nephritis. Kidney Int. 2003, 
63
, S.1382-1392,  
85 Nozik ES, Huang YC, Piantadosi CA: L-Arginine enhances injury in the 
isolated rappit lung during hypoxia. Respir Physiol. 1995, 
100
, S.63-74,  
86 Neilly PJ, Kirk SJ, Gardiner KR et al.: Manipulation of the L-arginine-nitric 
oxide pathway in experimental colitis. BR J Surg. 1995, 
82
, S.1188-1191,  
87 Zhang F, Casey RM, Ross ME, Iadecola S: Aminoguanidine ameliorates and 
L-arginine worsens brain damage from intraluminal middle cerebral artery 
occlusion. Stroke. 1996, 
27
, S.317-323,  
88 Reyes AA, Porras BH, Chasalow FI, Klahr S: L-Arginine decreases the 
infiltration of the kidney by macrophages in obstructive nephropathy and 
puromycin-induced nephrosis. Kidney Int. 1994, 
45
, S.782-787,  
89 Reyes AA, Klahr S: Dietary supplementation of L-arginine ameliorates renal 
hypertrophy in rats fed a high-protein diet. Proc Soc Exp Biol Med. 1994, 
206
, S.157-161,  
90 Katoh T, Takahashi k, Klahr S, et al.: Dietary supplementation with L-
arginine ameliorates glomerular hypertension in rats with subtotal 
nephrectomy. J Am Soc Nephrol. 1994, 
4
, S.1690-1694,  
91 Wu G, Meininger CJ: Arginine nutrition and cardiovascular function. J Nutr. 
2000, 
130
, S.2626-2629,  
92 De Nicolal, Bellizzi V, Minutolo R, et al.: Randomized, double-blind, placebo-
controlled study of arginine supplementation in chronic renal failure. 
Kidney Int. 1999, 
56
, S.674-684,  
93 Eisenberger: Abstract. J Am Soc Nephrol. 1999, 
10
, S.727-728A,  
94 Ketteler M, Ikegaya N, Brees DK, Border WA, Noble NA: L-arginine 
metabolism in immune-mediated glomerulonephritis in the rat. Am J 
Kidney Dis. 1996, 
28
, S.878-887,  

---

 
94
95 Narita I, Border WA, Ketteler M, Ruoslahti E, Noble NA: L-arginine may 
mediate the therapeutic effects of low protein diets. Proc Natl Acad Sci 
USA. 1995, 
92
, S.4552-4556,  
96 Yamamoto T, Noble NA, Miller DE, Border WA: Sustained expression of 
TGF-beta 1 underlies development of progressive kidney fibrosis. Kidney 
Int. 1994, 
45
, S.916-927,  
97 Benigni A, Perico N, Remuzzi G: Enothelin antagonists and renal protection. 
J Cardiovasc Pharmacol. 2000, 
35
, S.75-78,  
98 Sporn MB, Roberts AB: A major advance in the use of growth factors to 
enhance wound healing. J Clin Invest. 1993, 
92
, S.2565-2566,  
99 Romberger DJ: Fibronectin. Int J Biochem Cell Biol. 1997, 
29
, S.939-943,  
100 Baricos WH, Cortez SL, El-Dahr SS, Schnaper HW: ECM degradation by 
cultured human mesangial cells is mediated by a PA/plasmin/MM-2 
cascade. Kidney Int. 1995, 
47
, S.664-671,  
101 Eitzman DT, McCoy RC, Zheng X, Fay WP, Shen T, Ginsburg D, Simon 
RH: Bleomycin-induced pulmonary fibrosis in transgenic mice that either 
lack or overexpress the murine plasminogen activator inhibitor-1 gene. J 
Clin Invest. 1996, 
97
, S.232-237,  
102 Yamamoto T, Mundy CA, Wilson CB: Quantitative and qualitative studies of 
antibody induced mesangial cell damage in the rat. Kidney Int. 1987, 
32
, 
S.514-525,  
103 Eberhadt W, Beeg T, Beck KF et al.: Nitric oxide modulates expression of 
metalloproteinase-9 in rat mesangial cells. Kidney INt. 2000, 
57
, S.59-69,  
104 Arnal FJ, Warin L, Miche JB: Determinants of aortic cyclic guanosine 
monophosphate in hypertension induced by chronic inhibition of nitric 
oxide synthase. J Clin Invest. 1992, 
90
, S.647-652,  
105 Frei U, Schober-Halstenberg HJ: Nierenersatztherapie in Deutschland. 
Band QuaSi-Niere Jahresbericht 2001/2002. Berlin ,  
106 United States Renal Data Systems: Annual Data Report 2003. Minneapolis, 
USA,  
107 Green LC, Wagner DA, Glogowki J et al.: Analysis of nitrate, nitrite and 
15N-nitrate in biological fluids. Anal Biochem. 1982, 
126
, S.131-138,  

---

 
95
108 Watanabe N, Kamei S, Ohikubo A et al.: Urinary protein as measured with 
a pyrogallol-molybdate complex, manually and in a Hitachi 726 automatic 
analyzer. Clin Chem. 1986, 
32
, S.1551-1554,  
109 Watanabe G, Tomiyama H, Doba N: Effects of oral administration of L-
arginine on renal function in patients with heart failure. J Hypertens. 
2000, 
18
, S.229-234,  
110 Maxwell AJ, Cooke JP: Cardiovascular effects of L-arginine. Curr Opin 
Nephrol Hypertens. 1998, 
7
, S.63-70,  
111 Sigmon DH, Gonzales-Feldman E, Cavasin MA, Potter DL, Beierwal WH: 
Role of nitric oxide in the renal hemodynamic response to unilateral 
nephropathy. J Am Soc Nephrol. 2004, 
15(6)
, S.1413-1420,  
112 Six I, Van Belle E, Bordet R, Corseaux D, Callebert J, Dupuis B, Bauters C, 
Bertrand ME: L-Arginine and L-NAME have no effects on the 
reendotheliazation process after arterial balloon injury. Cardiovascular 
Research. 1999, 
43
, S.731-738,  
113 Ashab I, Peer G, Blum M et al.: Oral administration of L-arginine and 
captopril in rats prevents chronic renal failure by nitric oxide production. 
Kidney Int. 1995, 
47
, S.1515-1521,  
114 Krumenacker JS, Hanafy KA, Murad F: Regulation of nitric oxide and 
soluble guanylyl cyclase. Brain Res Bull. 2004, 
62(6)
, S. 505-15,  
115 Marletta, MA: Nitric oxide synthase structure and mechanism. J Biol Chem. 
1993, 
268
, S. 12231- 12234,  
116 Murad, F: Cellular signaling with nitric oxide and cyclic GMP. Braz J Med 
Biol Res. 1999, 
32
 (11), S. 1317-1327,  
117 Nathan C, Xie QW: Regulation of biosynthesis of nitric oxide. J Biol Chem. 
1994, 
269
, S. 13725- 13728,  
118 Malinski T, Taha Z: Nitric oxide release from a single cell measured in situ 
by a porphyrinic-based microsensor. Nature. 1992, 
358
 (6388), S. 676-
678, 

---

 
96
119 Sandau KB, Brune B: Molecular actions of nitric oxide in mesangial cells. 
Histol Histopathol. 2000, 
15(4)
, S. 1151-1158,  
120 Murad F: The excitement and rewards of research with our discovery of  
some of the biological effects of nitric oxide. Circ Res. 2003, 
92(4)
, S. 339-
341,  
121 Radi R, Beckman JS, Bush KM, Freeman BA: Peroxynitrite oxidation of  
sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol  
Chem. 1991, 
266(7)
, S. 4244-4250,  
122 Lowenstein CJ, Dinerman JL, Snyder SH: Nitric oxide: A physiologic  
messenger. Ann Intern Med. 1994; 
120(3)
, S. 227-237 

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97
7 
Erklärung an Eides Statt 
 
Die vorliegende Arbeit ist von mir selbst und ohne die unzulässige Hilfe Dritter 
verfaßt worden. Sie stellt auch in Teilen keine Kopie anderer Arbeiten dar und 
die benutzten Hilfsmittel sowie die Literatur sind vollständig angegeben. 
 
Berlin, den 16.12.2004 

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98
8 Publikationsverzeichnis 
 
 
Originalarbeiten 
 
1. H. Peters, U. Daig, M. Rückert, F. Schäper, L. Liefeldt, S. Krämer H.-H. 
Neumayer.  NO mediates the antifibrotic action of L-arginine supplementation in 
acute anti-thy-1 glomerulonephritis.   
Kidney Int 64: 509-518 (2003)   
 
 
 
 
 
 
 
2. H. Peters, R. Eisenberg, U. Daig, J. Gaedeke, L. Liefeldt, S. Krämer, H.-H. 
Neumayer.  Platelet inhibition limits TGF-ß overexpression and matrix 
expansion following induction of anti-thy-1 glomerulonephritis.   
Kidney In 65: 2238-48 (2004)   
 
 
 
 
 
 
 
 
Abstracts/Poster 
 
1. H. Peters, R. Eisenberg, U. Daig, M. Rückert und H.-H. Neumayer.  
Spezifische Thrombozytenhemmung vermindert TGF-ß-Überexpression bei 
anti-thy-1-Glomerulonephritis (GN). Med. Klinik 92: Abstract-Band 1: p 161 
(2001) 
 
2. H. Peters, U. Daig, F. Schäper, M. Rückert, J. Gaedeke, S. Krämer and H.-H. 
Neumayer.  The beneficial effect of L-arginine supplementation in experimental 
glomerulonephritis is mainly mediated by nitric oxide.  Kidney Blood Press Res 
24: p 226 (2001) 
 
3. H. Peters, R. Eisenberg, U. Daig, M. Rückert, J. Gaedeke and H.-H. 
Neumayer.  Specific platelet inhibition limits matrix accumulation following 
induction of acute anti-thy-1 glomerulonephritis (GN).  Kidney Blood Press Res 
24: p 268 (2001) 
 

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99
4. H. Peters, U. Daig, F. Schäper, M. Rückert, J. Gaedeke, S. Krämer and H.-H. 
Neumayer.  Nitric oxide mediates antifibrotic actions of L-arginine 
supplementation following induction of experimental glomerulonephritis.  J Am 
Soc Nephrol 12: p 713A (2001) 
 
5. H. Peters, R. Eisenberg, U. Daig, M. Rückert and H.-H. Neumayer.  Specific 
platelet inhibition limits TGF-ß overexpression following induction of anti-thy-1 
glomerulonephritis.  J Am Soc Nephrol 12: p 713A (2001) 
 
6. H. Peters, U. Daig, F. Schäper, M. Rückert, J. Gaedeke, S. Krämer und H.-H. 
Neumayer. Stickoxid (NO) vermindert die Überexpression von TGF-ß nach 
Induktion von anti-thy-1-Glomerulonephritis (GN). Med. Klinik 93: Abstract-Band 
1: p 122 (2002) 
 
7. H. Peters, S. Martini, M. Rückert, Y. R. Wang, U. Daig, S. Krämer, H.-H. 
Neumayer Matrix expansion in acute anti-thy-1 glomerulonephritis is partly 
mediated by lymphocytes. Kidney Blood Press Res 25: p 158 (2002) 
 
8. S. Krämer, S. Martini, R. Woydt, M. Rückert, Y. R. Wang, U. Daig, F. 
Shimizu, H. Kawachi, H-H. Neumayer, H. Peters.  MMF versus enalapril in 
chronic-progressive anti-thy-1 glomerulonephritis. Kidney Blood Press Res 25: 
p 160 (2002) 
 
9. H. Peters, S. Martini, M. Rückert, Y. R. Wang, U. Daig, S. Krämer, H.-H. 
Neumayer. Lymphocytes mediate partly matrix expansion in experimental 
mesangioproliferative glomerulonephritis (GN). J Am Soc Nephrol 13: p 133A 
(2002) 
 
10. S. Krämer, S. Martini, R. Woydt, M. Rückert, Y. R. Wang, U. Daig, F. 
Shimizu, H. Kawachi, H-H. Neumayer, H. Peters.  Effect of MMF on chronic 
progressive anti-thy-1 glomerulonephritis: Comparison with ACE inhibition. J 
Am Soc Nephrol 13: p 542A (2002) 
 

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100
11. S. Martini, S. Krämer, M. Rückert, Y. Wang, U. Daig, H.-H. Neumayer, H. 
Peters. Antifibrotischer Effekt von FTY720 bei akuter Anti-thy-1-
Glomerulonephritis. Med. Klinik 98: Abstract-Band 1: p 079 (2003)  
 
12. S. Krämer, S. Martini, R. Woydt, M. Rückert, Y. Wang, U. Daig, F. Shimizu, 
H. Kawachi, H.-H. Neumayer and H. Peters.  MMF is as effective as enalapril in 
slowing the progression of chronic anti-thy-1 glomerulonephritis. Nephrol Dial 
Transpl 18: 588 (2003) 

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101
Danksagung 
 
Mein Dank gilt dem gesamten Team des Nephrologischen Forschungslabors, 
Campus Charité Mitte. Ohne sie alle wäre diese Arbeit nicht gelungen. 
 
Vor allem Tanja Loof und Stefanie Krämer bin ich für die exzellente 
Unterstützung bei zahlreichen laborchemischen Herausforderungen sehr 
verbunden, Matthias Rückert für seine geduldigen Erläuterungen, Sebastian 
Martini für die vielen humorvolle Momente, die in mancher Durststrecke sehr 
bereichernd waren, Pia Hambach und Christine Lehmann für die kollegiale 
Einführungsarbeit sowie Andrej Karpinski für seine unermüdliche technical and 
mental assistance bei problemorientierter Rechnertherapie.  
 
Mein besonderer Dank gilt meinem Doktorvater Harm Peters, der die 
Durchführung dieser Arbeit möglich gemacht hat, mir mit Rat und Hilfe zur Seite 
stand und auch für produktive wissenschaftliche Diskussionen immer ein 
kompetenter Ansprechpartner war.