1 Division of Nephrology, Charité, Campus Mitte, Humboldt-University, D-10098 Berlin, Germany; and 2 Department of Cell Biology and Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
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ABSTRACT |
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Moderate alcohol consumption has shown
beneficial effects in experimental and human cardiovascular disease.
With the use of rat models of acute and chronic progressive anti-thy1
glomerulonephritis (GN), we tested the hypothesis that moderate alcohol
intake is protective in renal fibrotic disease. In acute anti-thy1 GN,
untreated nephritic rats showed marked mesangial cell lysis and induced nitric oxide production at day 1 and high proteinuria,
glomerular matrix accumulation, and transforming growth factor
(TGF)-1, fibronectin, and plasminogen activator
inhibitor (PAI)-1 expression at day 7 after disease
induction, respectively. In animals 15 wk after induction of chronic
progressive anti-thy1 GN, disease was characterized by significantly
reduced renal function, persisting albuminuria as well as increased
glomerular and tubulointerstitial matrix expansion,
TGF-
1, fibronectin, and PAI-1 protein expression. In
both anti-thy1 GN models, an ethanol intake of ~2 ml per day and
animal was achieved, however, disease severity was not significantly altered by moderate alcohol consumption in any of the protocols. In
conclusion, moderate alcohol intake does not influence renal matrix
protein production and accumulation in acute and chronic progressive
anti-thy1 glomerulofibrosis. The study suggests that, in contrast to
cardiovascular disorders, moderate alcohol consumption might not
provide specific protection in renal fibrotic disease.
fibrosis; transforming growth factor-; inducible nitric oxide
production; beer
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INTRODUCTION |
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NUTRITION PLAYS a major role in human health and disease. Modifying food and fluid intake was probably one of the first approaches humankind used to prevent, influence, or treat its various diseases. For renal disorders, beneficial effects of dietary modifications have been documented, mainly in experimental settings, for the intake of calories, proteins, certain amino acids, lipids, minerals, and vitamins (2, 3, 22). In cardiovascular disease, positive effects of moderate alcohol intake have been documented in numerous experimental and human studies (12, 20, 21, 36), whereas only little is known about its action on the course of kidney disorders.
As for cardiovascular disease, pathological expansion of extracellular
matrix proteins is a hallmark of acute and chronic renal disease
(4, 17). Glomerular and tubulointerstitial matrix
accumulation result from an increase in the production of matrix
proteins such as fibronectin, biglycan, and collagens; a decrease of
matrix protein degradation by increased production of protease
inhibitors such as plasminogen activator inhibitor (PAI)-1; and an
overexpression of matrix-binding integrins on the cell surface
(4, 25). Overproduction of the cytokine transforming
growth factor (TGF)- has been identified as a key feature of tissue
fibrosis wherever it occurs. While in acute renal disease TGF-
overexpression and matrix deposition are transient and reversible,
chronic renal disease is characterized by ongoing tissue injury
resulting in persisting TGF-
overproduction and progressive renal
fibrosis and insufficiency (4). This concept is reflected
exemplarily in the rat model of anti-thy1 glomerulonephritis. In
animals with two kidneys, anti-thy1 antibody injection leads to acute
and reversible mesangioproliferative glomerulonephritis (1), whereas in uninephrectomized rats, injection of
anti-thy1 antibody results in persisting glomerulosclerosis and
progressive tubulointerstitial fibrosis (23), which may be
related to a continuous hyperfiltration injury of the remaining kidney.
Because cardiovascular and kidney disorders share a number of
similarities at the cellular and molecular level, we hypothesized that
moderate alcohol intake may limit TGF- overexpression and matrix
expansion in renal disease. To test this hypothesis, we administered 40 ml beer/day to rats with acute or chronic progressive anti-thy1
glomerulonephritis. In acute anti-thy1 glomerulonephritis, alcohol
actions on the initial mesangial cell injury and subsequent matrix
expansion were determined (day 1 and day 7 after
antibody injection, respectively). In chronic anti-thy1
glomerulonephritis, ethanol's effects on renal function, glomerular
sclerosis, and tubulointerstitial fibrosis were analyzed 15 wk after
disease induction.
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METHODS |
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Materials
Unless otherwise indicated, materials, chemicals, or culture media were purchased from Sigma-Aldrich (Taufkirchen, Germany).Animals
Male Wistar rats (180-250 g) obtained from Charles River (Sulzfeld, Germany) were fed a normal protein diet (22.5% protein, Altromin, Lage, Germany) for at least 3 days before the start of the experiment to allow equilibration. Animal care and treatment were in conformity with the guidelines of the American Physiological Society and approved by local authorities. Animals were housed in a constant-temperature room with a 12:12-h light-dark cycle. Body weight was determined at the beginning and end of each experiment. Food, beer, and water intakes were monitored daily.Induction of Acute and Chronic Progressive Anti-Thy1 Glomerulonephritis
Acute anti-thy1 glomerulonephritis was induced by tail vein injection of the monoclonal antibody OX-7 (1 mg/kg body wt in PBS) as previously described (29). For chronic progressive glomerulonephritis, one kidney was surgically removed and the monoclonal antibody mAb 1-22-3 (4 mg/kg body wt in PBS) was intravenously injected 3 days later. In the kidney, OX-7 and mAb 1-22-3 antibodies bind to a thy1-like antigen (although to different epitopes) on the surface of mesangial cells and cause complement- and nitric oxide (NO)-dependent cell lysis (1, 23, 24). Control animals were injected with equal volumes of PBS only.Production of OX-7 and mAb 1-22-3
OX-7 and mAb 1-22-3 were produced from hybridoma cell lines as previously described (29). The antibodies were diluted in PBS (pH 7.4) and stored atModerate Alcohol Consumption
A moderate alcohol intake was achieved by supplying 40 ml beer (4.9% ethanol, 23 bitter units, expressing the bitterness of the beer's taste) per day and rat. The beer was provided every late afternoon, and in general the animals started drinking immediately. In addition, the animals had free access to tap water. This approach results in a daily intake of ~2 ml ethanol/animal, which, for rats, constitutes moderate alcohol intake (9).Experimental Design
In protocol 1, the action of moderate alcohol intake on early mesangial cell lysis (protocol 1A, injury phase, day 1) and on the subsequent matrix expansion (protocol 1B, matrix expansion phase, day 7) was analyzed in rats following the induction of acute anti-thy1 glomerulonephritis. In protocol 2, the effect of moderate alcohol consumption was investigated in rats with chronic progressive anti-thy1 glomerulonephritis (progression from acute glomerular to chronic tubulointerstitial fibrosis) 15 wk after disease induction.In experiments 1B and 2, the histological grading
of renal matrix accumulation was paralleled by protein measurements of
the key fibrosis mediator and marker TGF-. In addition, renal
expression of the matrix protein fibronectin was measured as an
indicator of matrix protein production. The protease inhibitor PAI-1
was used as a sensitive marker of the matrix-degrading system.
TGF-
1, fibronectin, and PAI-1 expression were measured
at the protein level in the supernatant of cultured glomeruli or minced
cortical tissue harvested from individual animals. The interaction of
ethanol with inducible NO production was tested in vivo in
protocol 1A (NO-mediated mesangial cell damage) and in vitro
in protocols 1B and 2 (stimulation of cultured
glomeruli of cortical tissue with LPS).
Protocol 1A
Effect of moderate alcohol intake on the injury phase of acute anti-thy1 glomerulonephritis (day 1 after antibody injection). Five days before antibody injection, Wistar rats were assigned to the following groups: 1) PBS-injected controls (control; n = 4); 2) anti-thy1 antibody-injected animals, no treatment (aGN; n = 8); and anti-thy1 antibody-injected rats plus moderate alcohol intake (aGN + C2H5OH; n = 8).
One day after antibody injection, the histological degree of mesangial cell lysis as well as the release of basal and LPS-stimulated nitrite production of cultured glomeruli were analyzed. At this point, mesangial cell lysis is complete and inducible glomerular NO production is markedly increased (28).Protocol 1B
Effect of moderate alcohol intake on the matrix expansion phase of anti-thy1 glomerulonephritis (day 7 after antibody injection). One day after antibody injection, when the mesangial cell lysis had occurred and the fibrotic response had started (28), Wistar rats were assigned to the following groups: 1) control (n = 4); 2) aGN (n = 8); and 3) aGN + C2H5OH (n = 8).
Seven days after disease induction, histological glomerular matrix accumulation and production of nitrite, TGF-Protocol 2
Effect of moderate alcohol intake on progression from acute to chronic progressive anti-thy1 glomerulonephritis (15 wk after antibody injection). Five weeks after uninephrectomy and antibody injection, Wistar rats were treated as follows: 1) uninephrectomized, PBS-injected controls (control; n = 4); 2) uninephrectomized, anti-thy1 antibody-injected animals, no treatment (cGN; n = 10); and 3) uninephrectomized, anti-thy1 antibody-injected rats plus moderate alcohol intake (cGN + C2H5OH; n = 10).
Fifteen weeks after induction of chronic anti-thy1 glomerulonephritis, parameters of renal function [glomerular filtration rate (GFR), serum creatinine, and blood urea nitrogen (BUN)] and indexes of glomerular and tubulointerstitial matrix accumulation (histological matrix score, glomerular and cortical protein expression of TGF-Measurement of Systolic Blood Pressure and Albuminuria
In animals with chronic anti-thy1 glomerulonephritis, systolic blood pressure was measured 2 days before death in conscious animals by the tail-cuff method as previously described (29). Because acute anti-thy1 glomerulonephritis has been shown to be normotensive (29), blood pressure was not measured in this model. In both acute and chronic anti-thy1 glomerulonephritis, a 24-h urine was collected from each rat the day before death, using metabolic cages. Albuminuria was measured using a microplate technique and a rabbit anti-rat albumin peroxidase-conjugated antibody (19). Albuminuria is expressed as milligrams of protein per 24 hours.Death
At the end of each experiment, the animals were anesthetized with ether. After a midline abdominal incision, 5-10 ml blood were drawn from the abdominal aorta and the kidneys were subsequently perfused with 30 ml ice-cold PBS. For histological examination, cortical tissue was fixed in 10% neutral buffered formalin.Measurement of Renal Function and Serum Ethanol Concentrations
Serum and urine creatinine, BUN, and serum ethanol concentrations were measured spectrophotometrically in enzyme-based assays. GFR was calculated on the basis of serum and urinary creatinine concentration and the corresponding urinary volume.Production of TGF-1, Fibronectin, and PAI-1 by
Glomeruli or Cortical Tissue in Culture
Light Microscopy
All microscopic examinations were performed in a blinded fashion. Three-micrometer sections of paraffin-embedded tissue were stained with periodic acid-Schiff (PAS). For calculation of mesangial cell lysis, the number of the remaining cell nuclei was counted in 30 glomeruli of 80- to 100-µm diameter from each animal. Glomerular matrix expansion was evaluated by rating the mesangial matrix-occupying area of 30 glomeruli from each rat using the following scoring system: 1 = 0-25%, 2 = 26-50%, 3 = 51-75%, and 4 = 76-100%. For estimation of renal matrix expansion in chronic progressive anti-thy1 glomerulonephritis, a combined glomerular and tubulointerstitial fibrosis score was used. Glomerular matrix accumulation was rated as described above. Tubulointerstitial matrix deposition was assayed in 20 randomly selected cortical areas per sample observed at ×250 magnification using the following scale: 0 = normal, 1 = lesions involving <10% of cortical area, 2 = involving 10-30%, 3 = involving 31-50%, and 4 = involving >50%, respectively. The individual renal fibrosis score was derived by adding the mean glomerular and tubulointerstitial matrix index of each animal.Measurement of TGF-1, Fibronectin, and PAI-1
Measurement of Nitrite
Nitrite is a stable end-product of NO and served as an indicator of endogenous NO synthesis (25). Nitrite levels in culture supernatant were measured by the Griess reaction (13). Briefly, 100 µl of sample were mixed with 100 µl Griess reagent [0.05% N-(1-naphthyl) ethylene diamine dihydrochloride, 0.5% sulfanilamide in 45% glacial acetic acid] in 96-well plates. After 10-min incubation in the dark, absorbance was read at 546 nm in an automated plate reader (MRX II, Dynex Technologies, Frankfurt/Main, Germany). Standard samples were prepared with sodium nitrite.Statistical Analysis
Data are expressed as means ± SE. Statistical analysis between the groups was performed by one-way ANOVA and subsequent t-test with Bonferroni correction for multiple comparison. A P value <0.05 was considered significant. ![]() |
RESULTS |
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Body Weight and Ethanol Intake
In protocols 1A and 1B, there were no significant differences in body weight gain between the groups investigated. In protocol 2, the body weight in week 15 was significantly lower in both groups of nephritic rats (cGN: 515 ± 11 g, cGN + C2H5OH: 509 ± 14 g) compared with the normal controls (574 ± 12 g, P < 0.05). This finding is probably a reflection of chronic renal disease and insufficiency in these two groups. In all three experiments, animals drank the 40 ml beer (4.9% ethanol) provided each day. This corresponds to a daily ethanol intake of 1.96 ml/rat, which, in the acute anti-thy1 animals, resulted in an approximate ethanol intake of 8-10 ml/kg body wt and, in the chronic anti-thy1 rats, of ~4-6 ml/kg body wt according to their weight gain over time, respectively. Because the term moderate alcohol intake covers a range of alcohol intakes and the 40 ml provided each day are close to the usual daily drinking volume of the rats, the amount of beer was not increased in protocol 2. In both protocols, ethanol concentrations in the blood taken the morning before death were below a detection limit of 0.02 per thousand. This confirms that the alcohol intake actually achieved was moderate.Protocol 1A
Effect of moderate alcohol intake on the injury phase of acute
anti-thy1 glomerulonephritis.
Compared with the normal control animals, injection of anti-thy1
antibody resulted in a significantly reduced glomerular cell number
(60.5 ± 1.8 vs. 45.8 ± 1.0, P < 0.001;
Fig. 1) as well as basal (1.1 ± 0.2 vs. 9.2 ± 1.5 nmol nitrite/ml, P < 0.001; Fig.
2A) and LPS-stimulated
glomerular NO production (3.5 ± 0.9 vs. 43.8 ± 3.9 nmol/ml,
P < 0.001; Fig. 2B), indicating the level of iNOS expression. Compared with the nephritic animals, the 6-day alcohol administration showed no significant action on disease activity
[glomerular cell number: 46.3 ± 1.5, basal and LPS-stimulated glomerular NO production: 8.0 ± 1.2 and 40.7 ± 4.3 nmol
nitrite/ml, respectively, all P = not significant (NS)
vs. aGN; Figs. 1 and 2].
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Protocol 1B
Effect of moderate alcohol intake on the matrix expansion phase of
acute anti-thy1 glomerulonephritis.
Seven days after injection of anti-thy1 antibody, disease was
characterized by a significant increase in albuminuria (46.8 ± 12.3 mg/24 h; Fig. 3), histological
matrix accumulation (matrix score 2.9 ± 0.1), and glomerular
production of TGF-1 (673 ± 53 pg/ml), fibronectin
(5,747 ± 338 ng/ml), and PAI-1 (1,095 ± 103 ng/ml,
P < 0.001 vs. aGN for all parameters; Fig.
4, A-D). Providing a 6-day moderate alcohol supply did not significantly limit albuminuria (46.1 ± 9.6 mg/24 h) or reduce the fibrotic response (matrix
score 3.0 ± 0.2, TGF-
1 680 ± 110 pg/ml,
fibronectin 5,730 ± 735 ng/ml, PAI-1 1,253 ± 92 ng/ml, all
P = NS vs. aGN; Figs. 3 and 4). Inducible NO production
of glomeruli in culture was not different between nephritic rats with
and without alcohol feeding (aGN: 3.9 ± 1.0 nmol nitrite/ml vs.
aGN + C2H5OH 4.4 ± 1.0 nmol
nitrite/ml, P = NS).
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Protocol 2
Effect of moderate alcohol intake on the progression from acute to
chronic progressive anti-thy1 glomerulonephritis.
As depicted in Fig. 5, chronic anti-thy1
glomerulonephritis shows glomerular sclerosis and a progress of the
matrix expansion into the tubulointerstitial space. Compared with the
nonnephritic controls, fibrotic disease in chronic anti-thy1
glomerulonephritis was characterized by moderately elevated blood
pressure (124 ± 2 vs. 138 ± 7 mmHg, P < 0.01), persisting high albuminuria (39 ± 11 vs. 128 ± 31 mg/24 h; Fig. 6), increased serum
creatinine (0.5 ± 0.1 vs. 1.0 ± 0.2 mg/dl; Fig.
7A) and BUN (57 ± 4 vs.
102 ± 25 mg/dl; Fig. 7B), and reduced GFR (2.3 ± 0.1 vs. 1.3 ± 0.3 ml/min; Fig. 7C; all parameters
P < 0.05 vs. control). The renal matrix score was
markedly increased (control 1.2 ± 0.3 vs. cGN 3.5 ± 0.6, P < 0.05; Fig. 5). In addition, nephritic rats showed significantly higher glomerular expression of TGF-1
(79 ± 17 vs. 170 ± 31 pg/ml; Fig.
8A), fibronectin (6,442 ± 413 vs. 12,632 ± 2,905 ng/ml; Fig. 8B), and PAI-1
(194 ± 14 vs. 430 ± 60 ng/ml; Fig. 8C;
P < 0.05 vs. cGN for all parameters), respectively. At the tubulointerstitial level, protein expression was increased significantly for TGF-
1 (37 ± 3 vs. 157 ± 35 pg/ml; Fig. 9A), fibronectin
(5,514 ± 485 vs. 9,909 ± 1,356 ng/ml; Fig. 9B),
and PAI-1 (443 ± 33 vs. 855 ± 139 ng/ml; Fig.
9C; P < 0.05 for all parameters).
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DISCUSSION |
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Although alcohol consumption is common among the general population, only little is known about its effect on the course of renal disease. This contrasts with cardiovascular disorders, where several epidemiological human studies have found that moderate alcohol intake, ranging from one to two drinks per day, is associated with a lower risk of coronary heart disease, ischemic stroke, dementia, and total mortality, especially in elderly men and women (12, 20, 21, 32). In experimental studies, furthermore, moderate ethanol intake reduces blood pressure and subsequent renal vascular injury in spontaneously hypertensive rats (36). In a rabbit model of vascular balloon injury, moderate alcohol intake has been found to limit neointimal hyperplasia in a pressure-independent manner involving less local chemokine expression (10).
To extend these findings to renal disease, the present study employed
the rat model of anti-thy1 glomerulonephritis to test in vivo the
hypothesis that moderate alcohol consumption protects from acute and
chronic renal matrix accumulation and renal insufficiency. It must be
emphasized that experimental circumstances were varied in many ways to
allow detection of even small protective effects. These variations
included 1) the use of acute anti-thy1 glomerulonephritis, a
model in which glomerular matrix expansion is fast and marked and, as
recently shown, even small antifibrotic actions can be detected
(29); 2) the use of chronic progressive
anti-thy1 glomerulonephritis, in which fibrosis slowly progresses from
the glomerulus into the tubulointerstitium and little beneficial
actions mount up to a detectable level over time (23);
3) determination of the key fibrosis mediator
TGF-1, which, as shown recently, is a valid and
sensitive marker of renal matrix expansion (26, 29);
4) measurement of the matrix protein fibronectin and the
protease inhibitor PAI-1 to allow detection of potential antifibrotic
actions independent of TGF-
; and 5) analysis of renal
function and urinary protein excretion. However, in neither of the two
models nor on any parameter was moderate alcohol intake associated with
a beneficial effect. Because the mechanisms of matrix expansion in
various renal diseases are rather common, the findings of this study
may be relevant for fibrotic renal disease in general. However, the present study does not exclude potential benefits of moderate alcohol
intake in other renal models or human kidney disease.
The precise mechanism of how alcohol intake influences cardiovascular disease is not fully understood. Several pathways have been proposed and may be involved. Epidemiological studies suggest that moderate alcohol consumption influences cardiovascular risk factors, primarily blood pressure, but also plasma cholesterol and triglyceride levels, platelet function, and fibrinolytic parameters, thereby preventing initiation and progression of atherosclerosis (12, 20, 21). At the molecular and cellular level, ethanol's actions have been associated with the inhibition of proliferation of many cell types (5, 6, 11, 18), suppressed postprandial vascular smooth muscle cell hypertrophy, a downregulation of PAI-1 expression (15), increased expression of vascular endothelial growth factor and subsequent angiogenesis (16), and stimulation of endothelial NO production and action (35, 37). Taken together, most of these mechanisms involved in the beneficial actions of moderate alcohol intake converge in effects that would limit tissue matrix protein production and accumulation. For the present study, we therefore decided to test the effect of moderate alcohol intake on renal matrix expansion as a common downstream pathway rather than on an upstream "surrogate" parameter. Because matrix accumulation in cardiovascular and in kidney disease shares many similarities (4), the lack of any benefit of moderate alcohol intake in renal fibrosis is surprising. The reason for this important difference is not clear. One explanation could be that endothelial dysfunction, in which many protective effects of alcohol converge as well, may be less important for the course and progression of fibrotic renal disease.
In addition to matrix expansion, the present study analyzed the effect of moderate alcohol intake on renal inducible NO production for the reason that ethanol has been found to inhibit iNOS in several cell types in vitro (14, 33, 34). Induction of iNOS is a key injurious stimulus in several models of renal disease, including the injury phase of acute anti-thy1 glomerulonephritis, acute tubular necrosis, renal transplant rejection, and lupus nephritis of the MRL/lpr mouse strain (27). As a consequence of tissue injury, inducible NO production results in subsequently increased matrix expansion, as shown in acute anti-thy1 glomerulonephritis and chronic MRL/lpr lupus nephritis (28, 30). In the present study, moderate alcohol intake showed no effect on the in vivo induction of iNOS in the injury phase of anti-thy1 glomerulonephritis or on its in vitro activation in cultured glomerular and cortical tissue from fibrotic anti-thy1 animals. This solid finding is highly consistent with the results on renal matrix expansion in acute and chronic anti-thy1 glomerulonephritis.
Other than the amount of alcohol, some studies have suggested that there might be an association between the type of alcoholic beverage and prevention of cardiovascular disease. A strong case has been made for what is called the "French paradox." This term refers to the fact that the cardiovascular mortality rate in France is just approximately half of that of other Western countries, although the prevalence of risk factors is not very different (12). This phenomon has been related to the high consumption of red wine in France. Red wine contains polyphenol compounds, which are strong antioxidants and may mediate protective actions (12, 21). Furthermore, a recent study showed that red wine directly reduces vascular endothelin expression (7), which is a key growth factor in atherosclerosis. In the present study, beer was used to supply alcohol to rats with fibrotic renal disease. Beer contains high amounts of flavonoids, which are strong antioxidants as well (8, 12). However, it has to be pointed out that a possible superiority of one type of alcoholic beverage has never been investigated systematically, and most cohort studies do not support an association between the preferred kind of drink and the prevention of cardiovascular disease (12). Thus, in addition to the moderate alcohol intake achieved in this study, the choice of beer as an alcoholic beverage is probably of less importance for the interpretation of its results.
In conclusion, moderate alcohol intake does not influence renal matrix expansion in anti-thy1 models of acute and chronic progressive glomerulofibrosis. The effect of alcohol intake in various doses, in other renal models and human kidney disease warrants further investigation.
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ACKNOWLEDGEMENTS |
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The technical assistance of T. Loof and A. Stössel is highly appreciated.
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FOOTNOTES |
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This study was supported by a grant from the Wissenschaftsföderung der Deutschen Brauwirtschaft e.V. and in part by a grant from the Deutsche Forschungsgemeinschaft (PE 558/2-1).
Address for reprint requests and other correspondence: H. Peters, Division of Nephrology, Charité, Campus Mitte, Schumannstrasse 20/21, D-10098 Berlin, Germany (E-mail: Harm.Peters{at}charite.de).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajprenal.00328.2002
Received 10 September 2002; accepted in final form 28 January 2003.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Bagchus, WM,
Hoedemaeker PJ,
Rozing J,
and
Bakker WW.
Glomerulonephritis induced by monoclonal anti-thy 1.1 antibodies.
Lab Invest
55:
680-687,
1986[ISI][Medline].
2.
Bergstrom, J.
Nutrition in chronic renal failure.
Nefrologia
20, Suppl3:
52-58,
2000[Medline].
3.
Bircher, G.
Nutrition in chronic renal failure.
In: Clinical Nephrology, edited by Johnson RJ,
and Feehally J.. New York: Harcourt, 2000, p. 75.1-75.7.
4.
Border, WA,
and
Noble NA.
Transforming growth factor in tissue fibrosis.
N Engl J Med
331:
1286-1292,
1994
5.
Chen, J,
Clemens DL,
Cederbaum AI,
and
Gao B.
Ethanol inhibits the JAK-STAT signaling pathway in freshly isolated rat hepatocytes but not in cultured hepatocytes or HepG2 cells: evidence for a lack of involvement of ethanol metabolism.
Clin Biochem
34:
203-209,
2001[ISI][Medline].
6.
Choudhry, MA,
Messingham KA,
Namak S,
Colantoni A,
Fontanilla CV,
Duffner LA,
Sayeed MM,
and
Kovacs EJ.
Ethanol exacerbates T cell dysfunction after thermal injury.
Alcohol
21:
239-243,
2000[ISI][Medline].
7.
Corder, R,
Douthwaite JA,
Lees DM,
Khan NQ,
Viseu Dos Santos AC,
Wood EG,
and
Carrier MJ.
Endothelin-1 synthesis reduced by red wine.
Nature
414:
863-864,
2001[ISI][Medline].
8.
Denke, MA.
Nutritional and health benefits of beer.
Am J Med Sci
320:
320-326,
2000[ISI][Medline].
9.
El Mas, MM,
and
Abdel-Rahman AA.
Radiotelemetric evaluation of hemodynamic effects of long-term ethanol in spontaneously hypertensive and Wistar-Kyoto rats.
J Pharmacol Exp Ther
292:
944-951,
2000
10.
Feng, AN,
Chen YL,
Chen YT,
Ding YZ,
and
Lin SJ.
Red wine inhibits monocyte chemotactic protein-1 expression and modestly reduces neointimal hyperplasia after balloon injury in cholesterol-fed rabbits.
Circulation
100:
2254-2259,
1999
11.
Garriga, J,
Adanero E,
Fernandez-Sola J,
Urbano-Marquez A,
and
Cusso R.
Ethanol inhibits skeletal muscle cell proliferation and delays its differentiation in cell culture.
Alcohol
35:
236-241,
2000.
12.
Goldberg, IJ,
Mosca L,
Piano MR,
and
Fisher EA.
AHA Science Advisory: wine and your heart: a science advisory for healthcare professionals from the Nutrition Committee, Council on Epidemiology and Prevention, and Council on Cardiovascular Nursing of the American Heart Association.
Circulation
103:
472-475,
2001
13.
Green, LC,
Wagner DA,
Glogowski J,
Skipper PL,
Wishnok JS,
and
Tannenbaum SR.
Analysis of nitrate, nitrite and 15N-nitrate in biological fluids.
Anal Biochem
126:
131-138,
1982[ISI][Medline].
14.
Greenberg, SS,
Jie O,
Zhao X,
Wang JF,
and
Giles TD.
The potential mechanism of induction of inducible nitric oxide synthase mRNA in alveolar macrophages by lipopolysaccharide and its suppression by ethanol, in vivo.
Alcohol Clin Exp Res
22:
260S-265S,
1998[ISI][Medline].
15.
Grenett, HE,
Wolkowicz PE,
Benza RL,
Tresnak JK,
Wheeler-And CG,
and
Booyse FM.
Identification of a 251-bp fragment of the PAI-1 gene promoter that mediates the ethanol-induced suppression of PAI-1 expression.
Alcohol Clin Exp Res
25:
629-636,
2001[ISI][Medline].
16.
Gu, JW,
Elam J,
Sartin A,
Li W,
Roach R,
and
Adair TH.
Moderate levels of ethanol induce expression of vascular endothelial growth factor and stimulate angiogenesis.
Am J Physiol Regul Integr Comp Physiol
281:
R365-R372,
2001
17.
Klahr, S,
Schreiner G,
and
Ichikawa I.
The progression of renal disease.
N Engl J Med
318:
1657-1666,
1988[Abstract].
18.
Kotter, K,
and
Klein J.
Ethanol inhibits astroglial cell proliferation by disruption of phospholipase D-mediated signaling.
J Neurochem
73:
2517-2523,
1999[ISI][Medline].
19.
Magnotti, RA,
Stephens GW,
Rogers RK,
and
Pesce AJ.
Microplate measurement of urinary albumin and creatinine.
Clin Chem
35:
1371-1375,
1989
20.
Mazzaglia, G,
Britton AR,
Altmann DR,
and
Chenet L.
Exploring the relationship between alcohol consumption and non-fatal or fatal stroke: a systematic review.
Addiction
96:
1743-1756,
2001[ISI][Medline].
21.
Meister, KA,
Whelan EM,
and
Kava R.
The health effects of moderate alcohol intake in humans: an epidemiologic review.
Crit Rev Clin Lab Sci
37:
261-296,
2000[ISI][Medline].
22.
Mitch, WE.
Dietary therapy in uremia: the impact on nutrition and progressive renal failure.
Kidney Int Suppl
75:
S38-S43,
2000[Medline].
23.
Nakamura, T,
Obata J,
Kimura H,
Ohno S,
Yoshida Y,
Kawachi H,
and
Shimizu F.
Blocking angiotensin II ameliorates proteinuria and glomerular lesions in progressive mesangioproliferative glomerulonephritis.
Kidney Int
55:
877-889,
1999[ISI][Medline].
24.
Narita, I,
Border WA,
Ketteler M,
and
Noble NA.
Nitric oxide mediates immunologic injury to kidney mesangium in experimental glomerulonephritis.
Lab Invest
72:
17-24,
1995[ISI][Medline].
25.
Peters, H,
Border WA,
and
Noble NA.
Angiotensin II and L-arginine in tissue fibrosis: more than blood pressure.
Kidney Int
51:
1481-1486,
1997[ISI][Medline].
26.
Peters, H,
Border WA,
and
Noble NA.
Angiotensin II blockade and low protein diet produce additive therapeutic effects on experimental glomerulonephritis.
Kidney Int
57:
1493-1501,
1999[ISI].
27.
Peters, H,
Border WA,
and
Noble NA.
From rats to men: a perspective on dietary L-arginine supplementation in human renal disease.
Nephrol Dial Transplant
14:
1640-1650,
1999[Abstract].
28.
Peters, H,
Border WA,
and
Noble NA.
L-Arginine supplementation increases mesangial cell injury and subsequent tissue fibrosis in experimental glomerulonephritis.
Kidney Int
55:
2264-2273,
1999[ISI][Medline].
29.
Peters, H,
Noble NA,
and
Border WA.
Targeting TGF- overexpression in renal disease: maximizing the antifibrotic action of angiotensin II blockade.
Kidney Int
54:
1575-1583,
1998.
30.
Peters H, Rückert M, Krämer S, Border WA, Noble NA, and
Neumayer HH. L-Arginine supplementation accelerates
renal fibrosis and shortens life span in experimental lupus nephritis.
Kidney Int. In press.
31.
Rennard, SI,
Berg R,
Martin GR,
Foidart JM,
and
Robey PG.
Enzyme-linked immunoassay (ELISA) for connective tissue components.
Anal Biochem
104:
205-214,
1980[ISI][Medline].
32.
Ruitenberg, A,
van Swieten JC,
Witteman JC,
Mehta KM,
van Duijn CM,
Hofman A,
and
Breteler MM.
The Rotterdam Study.
Lancet
359:
281-286,
2002[ISI][Medline].
33.
Saibara, T,
Ono M,
Iwasaki S,
Maeda T,
Onishi S,
Hayashi-And Y,
and
Enzan H.
Effects of ethanol on L-arginine transport in rat Ito cells in relation to nitric oxide production.
Alcohol Clin Exp Res
25:
39S-45S,
2001[ISI][Medline].
34.
Syapin, PJ,
Militante JD,
Garrett DK,
and
Ren L.
Cytokine-induced iNOS expression in C6 glial cells: transcriptional inhibition by ethanol.
J Pharmacol Exp Ther
298:
744-752,
2001
35.
Utkan, T,
Yildiz F,
Ilbay G,
Ozdemirci S,
Erden BF,
Gacar N,
and
Ulak G.
Blood pressure and vascular reactivity to endothelin-1, phenylephrine, serotonin, KCl and acetylcholine following chronic alcohol consumption in vitro.
Fundam Clin Pharmacol
15:
157-165,
2001[ISI][Medline].
36.
Vasdev, S,
Ford CA,
Longerich L,
Parai S,
and
Gadag V.
Antihypertensive effect of low ethanol intake in spontaneously hypertensive rats.
Mol Cell Biochem
200:
85-92,
1999[ISI][Medline].
37.
Venkov, CD,
Myers PR,
Tanner MA,
Su M,
and
Vaughan DE.
Ethanol increases endothelial nitric oxide production through modulation of nitric oxide synthase expression.
Thromb Haemost
81:
638-642,
1999[ISI][Medline].