Oxidative stress, advanced glycation end products and residual renal function in the rat model of unilateral ureteral obstruction: effects of phlogenzym and losartan
Aim. Oxidative stress plays a role in the pathogenesis of ureteral obstruction. Methods. We studied parameters of oxidative status, levels of advanced glycation end products (AGEs), and contralateral (CL) kidney function in the rat model of unilateral ureteral obstruction (UUO). The effect of Phloge...
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Інститут молекулярної біології і генетики НАН України
2010
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| Цитувати: | Oxidative stress, advanced glycation end products and residual renal function in the rat model of unilateral ureteral obstruction: effects of phlogenzym and losartan / K.Jr. Sebekova, Jr.P. Blazicek, D. Syrova, S. Galbavy, R. Schinzel, A. Heidland, K. Sebekova // Вiopolymers and Cell. — 2010. — Т. 26, № 2. — С. 121-127. — Бібліогр.: 32 назв. — англ. |
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irk-123456789-1538792019-07-06T20:26:37Z Oxidative stress, advanced glycation end products and residual renal function in the rat model of unilateral ureteral obstruction: effects of phlogenzym and losartan Sebekova, K.Jr. Blazicek, Jr.P. Syrova, D. Galbavy, S. Schinzel, R. Heidland, A. Sebekova, K. Biomedicine Aim. Oxidative stress plays a role in the pathogenesis of ureteral obstruction. Methods. We studied parameters of oxidative status, levels of advanced glycation end products (AGEs), and contralateral (CL) kidney function in the rat model of unilateral ureteral obstruction (UUO). The effect of Phlogenzym (12 mg/day orally); losartan (20 mg/l in drinking water), and their combination was studied. Results. In placebo-administered UUO rats AGEs and malondialdehyde levels were higher than in the sham operated controls. Function of the CL kidney was slightly impaired, its collagen content and protein/deoxyribonucleic acid ratio (P/DNA) in the glomeruli increased. All treatments prevented the rise in collagen content, P/DNA ratio, and improved CL kidney function. Phlogenzym ameliorated lipid peroxidation and AGE levels. Conclusions. In the model of UUO systemically increased oxidative stress may play a role in development of tubulointerstitial fibrosis and in the functional impairment of the CL kidney. Suppression of the oxidative stress and blockade of angiotensin-1 receptors might mitigate the progression of obstructive uropathy. Оксидативний стрес відіграє значну роль у патогенезі обструкції сечоводу. Мета роботи полягала у вивченні параметрів оксидативного статусу, оцінюванні рівня кінцевих продуктів глікації і функціонування контралатеральної нирки на моделі щурів з унілатеральною обструкцією сечоводу (УОС). Методи. На моделі УОС досліджували ефекти флогензиму (12 мг в день орально) і лосартану (20 мг/л у питній воді), а також їхньої комбінації. Результати. У щурів з УОС, які отримували плацебо, рівень накопичення кінцевих продуктів глікації та малондіальдегіду виявився вищим, ніж у несправжньооперованих контрольних щурів. Функціонування контралатеральної нирки незначно погіршилося, концентрація колагену і співвідношення вмісту білок/дезоксирибонуклеїнова кислота (P/ DNA) у клубочку нирки підвищені. Обробка досліджуваними лікарськими засобами запобігала збільшенню вмісту колагену, зростанню показника співвідношення P/DNA та покращувала функціонування колатеральної нирки. Флогензим сприяв підвищенню рівня перекисного окиснення ліпідів та кінцевих продуктів глікації. Висновки. У моделі УОС систематичне збільшення оксидативного стресу може відігравати важливу роль у розвитку тубулоінтерстиційного фіброзу і порушенні функціонування контралатеральної нирки. Супресія оксидативного стресу та блокування рецептора ангіотензину-1 можуть послаблювати прогресію обструктивної уропатії. Оксидативный стресс играет значительную роль в патогенезе обструкции мочеточника. Цель работы состояла в изучении параметров оксидативного статуса, оценке уровня конечных продуктов гликации и функционирования контралатеральной почки на модели крыс с унилатеральной обструкцией мочеточника (УОМ). Методи. На модели УОМ исследовали эффекты флогензима (12 мг в день орально) и лосартана (20 мг/л в питьевой воде), а также их комбинации. Результаты. У крыс с УОМ, получавших плацебо, уровень конечных продуктов гликации и малондиальдегида оказался выше, чем у ложноооперованных контрольных крыс. Функционирование контралатеральной почки незначительно ухудшилось, концентрация коллагена и соотношение содержания белок/дезоксирибонуклеиновая кислота (P/DNA) в клубочке почки повысились. Обработка исследуемыми лекарственными средставами предотвращала увеличение содержания коллагена, показателя соотношения P/DNA и улучшала функционирование колатеральной почки. Флогензим способствовал возрастанию уровня перекисного окисления липидов и конечных продуктов гликации. Выводы. В модели УОМ систематическое увеличение оксидативного стресса может быть причиной развития тубулоинтерстиционного фиброза и нарушения функционирования контралатеральной почки. Супрессия оксидативного стресса и блокирование рецептора ангиотензина-1 можгут ослаблять прогрессию обструктивной уропатии. 2010 Article Oxidative stress, advanced glycation end products and residual renal function in the rat model of unilateral ureteral obstruction: effects of phlogenzym and losartan / K.Jr. Sebekova, Jr.P. Blazicek, D. Syrova, S. Galbavy, R. Schinzel, A. Heidland, K. Sebekova // Вiopolymers and Cell. — 2010. — Т. 26, № 2. — С. 121-127. — Бібліогр.: 32 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00014E http://dspace.nbuv.gov.ua/handle/123456789/153879 616.61-008.6 en Вiopolymers and Cell Інститут молекулярної біології і генетики НАН України |
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Biomedicine Biomedicine |
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Biomedicine Biomedicine Sebekova, K.Jr. Blazicek, Jr.P. Syrova, D. Galbavy, S. Schinzel, R. Heidland, A. Sebekova, K. Oxidative stress, advanced glycation end products and residual renal function in the rat model of unilateral ureteral obstruction: effects of phlogenzym and losartan Вiopolymers and Cell |
| description |
Aim. Oxidative stress plays a role in the pathogenesis of ureteral obstruction. Methods. We studied parameters of oxidative status, levels of advanced glycation end products (AGEs), and contralateral (CL) kidney function in the rat model of unilateral ureteral obstruction (UUO). The effect of Phlogenzym (12 mg/day orally); losartan (20 mg/l in drinking water), and their combination was studied. Results. In placebo-administered UUO rats AGEs and malondialdehyde levels were higher than in the sham operated controls. Function of the CL kidney was slightly impaired, its collagen content and protein/deoxyribonucleic acid ratio (P/DNA) in the glomeruli increased. All treatments prevented the rise in collagen content, P/DNA ratio, and improved CL kidney function. Phlogenzym ameliorated lipid peroxidation and AGE levels. Conclusions. In the model of UUO systemically increased oxidative stress may play a role in development of tubulointerstitial fibrosis and in the functional impairment of the CL kidney. Suppression of the oxidative stress and blockade of angiotensin-1 receptors might mitigate the progression of obstructive uropathy. |
| format |
Article |
| author |
Sebekova, K.Jr. Blazicek, Jr.P. Syrova, D. Galbavy, S. Schinzel, R. Heidland, A. Sebekova, K. |
| author_facet |
Sebekova, K.Jr. Blazicek, Jr.P. Syrova, D. Galbavy, S. Schinzel, R. Heidland, A. Sebekova, K. |
| author_sort |
Sebekova, K.Jr. |
| title |
Oxidative stress, advanced glycation end products and residual renal function in the rat model of unilateral ureteral obstruction: effects of phlogenzym and losartan |
| title_short |
Oxidative stress, advanced glycation end products and residual renal function in the rat model of unilateral ureteral obstruction: effects of phlogenzym and losartan |
| title_full |
Oxidative stress, advanced glycation end products and residual renal function in the rat model of unilateral ureteral obstruction: effects of phlogenzym and losartan |
| title_fullStr |
Oxidative stress, advanced glycation end products and residual renal function in the rat model of unilateral ureteral obstruction: effects of phlogenzym and losartan |
| title_full_unstemmed |
Oxidative stress, advanced glycation end products and residual renal function in the rat model of unilateral ureteral obstruction: effects of phlogenzym and losartan |
| title_sort |
oxidative stress, advanced glycation end products and residual renal function in the rat model of unilateral ureteral obstruction: effects of phlogenzym and losartan |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| publishDate |
2010 |
| topic_facet |
Biomedicine |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/153879 |
| citation_txt |
Oxidative stress, advanced glycation end products and residual renal function in the rat model of unilateral ureteral obstruction: effects of phlogenzym and losartan / K.Jr. Sebekova, Jr.P. Blazicek, D. Syrova, S. Galbavy, R. Schinzel, A. Heidland, K. Sebekova // Вiopolymers and Cell. — 2010. — Т. 26, № 2. — С. 121-127. — Бібліогр.: 32 назв. — англ. |
| series |
Вiopolymers and Cell |
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| fulltext |
BIOMEDICINE
Oxidative stress, advanced glycation end products and
residual renal function in the rat model of unilateral
ureteral obstruction: effects of phlogenzym and losartan
K. Sebekova, Jr., P. Blazicek1, D. Syrova2, S. Galbavy3, R. Schinzel4,
A. Heidland4, K. Sebekova5
St. Elisabeth and Barbara Hospital
5, Mauerstrabe, Halle/Saale, Germany, 06110
1Alpha Medical
49, Vlcie hrdlo, Slovakia, 81207
2Children Hospital
1, Limbova, Bratislava, Slovakia, 83340
3St. Elisabeth University of Health and Social Sciences
1, Namestie, maja, Bratislava, Slovakia, 81100
4University of Wurzburg
6, Oberdurrbacher Strabe, Wurzburg, Germany, 97080
5Slovak Medical University
12, Limbova, Bratislava, Slovakia, 83303
katarina.sebekova@szu.sk
Aim. Oxidative stress plays a role in the pathogenesis of ureteral obstruction. Methods. We studied
parameters of oxidative status, levels of advanced glycation end products (AGEs), and contralateral (CL)
kidney function in the rat model of unilateral ureteral obstruction (UUO). The effect of Phlogenzym
(12 mg/day orally); losartan (20 mg/l in drinking water), and their combination was studied. Results. In pla-
cebo-administered UUO rats AGEs and malondialdehyde levels were higher than in the sham operated con-
trols. Function of the CL kidney was slightly impaired, its collagen content and protein/deoxyribonucleic
acid ratio (P/DNA) in the glomeruli increased. All treatments prevented the rise in collagen content, P/DNA
ratio, and improved CL kidney function. Phlogenzym ameliorated lipid peroxidation and AGE levels. Con-
clusions. In the model of UUO systemically increased oxidative stress may play a role in development of
tubulointerstitial fibrosis and in the functional impairment of the CL kidney. Suppression of the oxidative
stress and blockade of angiotensin-1 receptors might mitigate the progression of obstructive uropathy.
Keywords: ureteral obstruction, advanced glycation end products, oxidative stress, malondialdehyde,
collagen.
Introduction. In the model of unilateral ureteral ob-
struction (UUO) altered hemodynamics, hypoxia, infil-
tration with macrophages, up-regulated renin-angio-
tensin-aldosterone system producing vasoactive com-
pounds, result in tubulointerstitial fibrosis of the
ligated kidney [1–3]. Angiotensin (Ang) II may
promote cell growth and fibrosis via overexpression of
growth factors and cytokines, and the induction of
oxidative stress [4]. The latter one is in the tu-
bulointerstitium of obstructed kidney reflected by
121
ISSN 0233-7657. Biopolymers and Cell. 2010. Vol. 26. N 2
Ó Institute of Molecular Biology and Genetics NAS of Ukraine, 2010
increased heme oxygenase-1 expression, accumulation
of Ne-(carboxymethyl)lysine (CML), and perturbation
of tubular antioxidants; and systemically by the rise in
plasma malondialdehyde (MDA) levels [5, 6]. The en-
hanced formation of reactive oxygen species (ROS)
may exert toxic effects in other tissues and organs. The
contralateral (CL) kidney, due to its compensatory hy-
pertrophy, might be the most susceptible.
Advanced glycation end products (AGEs) are for-
med on proteins by non-enzymatic glycation and/or
glycoxidation. With decreased renal function they ac-
cumulate in tissues and circulation, due to retention and
enhanced synthesis under exaggerated oxidative- and
carbonyl-stress [7, 8]. Interaction of AGEs with their
specific cell surface receptor RAGE leads to the pro-
duction of ROS, which accelerate formation of AGEs
[9]. Experimental studies suggest the interaction bet-
ween the AGE-RAGE and the renin-angiotensin sys-
tems [10]. In vitro, Ang II receptor 1 blockers (ARBs)
lower AGEs formation, and suppress the AGEs-
induced enhanced Ang 1 receptor protein [11, 12].
They also attenuate the accumulation of AGEs in vivo
[13, 14].
In studies on pig proximal tubular cells (LLC-PK1)
trypsin prevented the AGEs-induced cell hypertrophy
and accumulation of AGEs [15, 16]. In rodents
administration of proteases improved the course of
various renal diseases [17, 18]. Whether administration
of proteases interferes with AGEs and oxidative stress
in vivo remains unclear.
We investigated the possible involvement of the
systemically enhanced oxidative stress in relation to the
function and structure of the CL kidney, in the model of
UUO. AGE-lowering- and antioxidant-potential of the
above mentioned treatment modalities, and their com-
bination was studied.
Materials and methods. The trial was conducted
according to the guidelines for studies using laboratory
animals, after the approval by the local Ethics Board for
Experimental Animals (Bratislava).
Rats. Male Wistar rats (180–220 g, VELAS Praha,
Czech Republic) were caged under controlled hu-
midity, temperature, and light/dark cycle, with free ac-
cess to drinking water and food (SP1, Top Dovo, Czech
Republic). After induction of UUO rats were pair-fed to
the UUO placebo administered group.
Induction of unilateral ureteral obstruction. Forty
rats were subjected to UUO in i. p. thiopental narcosis.
Briefly, right ureter was liberated, ligated twice with
sterile silk, and cut between two ligations. Six sham-
operated rats served as controls (CTRL).
Experimental protocol. UUO rats were randomized
into 4 groups per 10 animals, administered during 14
days: a) placebo (UUO-P); b) a fixed mixture of pro-
teases (UUO-E, Phlogenzym, «MUCOS Pharma», Ger-
many) in a dose of 12 mg/day in 1 ml of tap water (each
dose contained 2.42 mg trypsin, 4.54 mg bromelain,
and 5.04 mg flavonoid rutosid); c) ARB (UUO-ARB,
Losartan, MSD, USA, 20 mg/l in drinking water); d)
combined treatment (UUO-COMB, both drugs in the
above mentioned dosage). Control and UUO-P rats we-
re gavaged by 1 ml of water.
Body weight and blood pressure (tail plethysmo-
graphy) was recorded. At sacrifice (thiopental narco-
sis), blood was sampled from abdominal aorta and urine
from bladder. Standard blood chemistry was determi-
ned (Vitros 250 analyzer, «J&J», USA). Plasma or
whole blood was stored at –70oC for determination of:
total antioxidant status (TAS) and glutathione peroxi-
dase activity (GPX), («Randox», UK); plasma MDA
[19] and lipofuscin (LF) [20] concentrations; and AGE
specific fluorescence [21]. CML concentration was
quantified with competitive ELISA using monoclonal
antibodies according to the method developed by «Ro-
che Diagnostika», Germany. One AGE unit (U) repre-
sented 50 % reduction in binding. Proteinuria was de-
termined by a pyrogallol red method.
Kidneys were weighed. Collagen content in renal
cortex was determined in formaline fixed paraffin em-
bedded slices, stained with hematoxilyne/eosine and
Van Gieson. The contrast red area stained as collagen
was expressed in per cent of the cortical tissue area with
aids of computerized video camera. In glomeruli
isolated by differential sieving method [22] the DNA
[23] and protein content [24] was determined.
Statistics. The data were tested for normality and
equality of variance, and compared either by one-way
analysis of variance (ANOVA) with post hoc Scheffe’s
test; or by Kruskal-Wallis with Mann-Whitney U-tests.
Results are given as mean ± SD, or as median, me-
an ± SD (not normally distributed data); p < 0.05 was
considered significant.
122
SEBEKOVA K.JR. ET AL.
Results and discussion. Role of accumulation of
AGEs in pathogenesis of UUO (Table). At sacrifice
the body weight of the UUO-P rats was lower than
that of CTRL rats. The weight of the CL kidney and
kidney/body weight ratio was comparable. UUO
resulted in hypertrophy of the glomeruli in CL
kidney, as indicated by rise of protein/DNA ratio
(Fig. 1, a). In LLC-PK1 cells, AGE-modified albu-
min induced cell hypertrophy via stimulation of pro-
tein synthesis and inhibition of its degradation [15,
16]. The latter one was, at least partially, caused by
the decline in lysosomal cathepsin activity, due to
down-regulation of mRNA levels [25]. Plasma AGE-
specific fluorescence (Table) and CML concentra-
tions (Fig. 2) were significantly higher in the UUO-P
rats than in the CTRL, but not on the account of plas-
ma albumin or glucose concentration. AGEs rose
despite only a moderate changes in plasma creatinine
levels. The rise in protein content of isolated glomeruli
may be causally linked to enhanced circulating AGE le-
vels, as supported by a direct relation between plasma
CML and P/DNA content (r = 0.567, p < 0.02).
In the cortex of CL kidney collagen content increased
5-fold (Fig. 1, b). Incubation of LLC-PK1 or immortali-
zed human kidney epithelial cells (IHKECs) with AGE-
modified BSA results in intracellular accumulation of
AGEs, associated with the induction of pro-fibrotic fac-
tors (overexpression of TGF-b1 mRNA, rise in TGF-b1
protein, enhanced activation of protein kinase C, and fib-
ronectin synthesis) [12, 15, 16]. Thus, elevated circu-
lating AGEs may contribute to rise in renal cortex col-
lagen content, as supported by a direct relation between
plasma CML and renal cortex collagen content (r =
= 0.918, p < 0.001). However, in the UUO model plasma
CML accumulates in spite of its enhanced renal excre-
tion (Fig. 2). UUO represents a nonproteinuric model of
123
RAT UUO MODEL: EFFECTS OF PHLOGENZYM AND LOSARTAN
Morphometric data, blood and urine chemistry
Parameter
CTRL
(n = 6)
UUO-P
(n = 10)
UUO-E
(n = 10)
UUO-ARB
(n = 9)
UUO-COMB
(n = 9)
ANOVA/K-W
F p
Body wt, g 240.0±3.4 203.5±5.1** 194.6±4.0** 210.4±3.4** 189.9±4.6** 16.16 0.001
CL kidney wt, mg 892±46 958±43 1038±48 982±55 967±36 0.19 0.943
CL kidney/body wt, mg/g 3.7±0.2 4.8±0.3 5.0±0.3 5.1±0.4 5.1±0.2 1.95 0.123
SBP, mm Hg 100.0; 96.7±3.1 100.0; 102.5±2.0 100.0; 102.5±1.5 100.0; 95.0±3.8 95.0; 94.4±2.8 7.70 0.100
Creatinine, mmol/l 46.5±1.2 66.7±3.3** 47.1±2.8++ 54.3±2.7 56.3±6.2 4.85 0.003
Urea, mmol/l 4.5±0.4 6.9±0.2** 4.7±0.3++ 5.9±0.6 5.2±0.3+ 7.77 0.001
Proteinuria, ng/mmol crea 81.3; 72.8±17.8 98.2; 124.0±21.2 62.0; 65.4±12.5 83.7; 70.3±15.2 54.4; 65.9±12.0 0.30 0.990
Glucose, mmol/l 7.1; 7.0±1.8 6.9; 7.3±0.6 6.6; 6.9±0.3 8.0; 8.6±0.7 7.1; 7.3±0.4 5.36 0.252
Albumin, g/l 29.5±0.6 29.2±0.6 28.0±0.6 29.3±0.8 30.8±0.9 1.86 0.141
Lipofuscin, AU 6.1; 6.6±0.9 10.4; 10.1±0.4** 7.3; 7.4±0.2++ 11.0; 10.9±0.4** 6.8; 7.4±0.3++ 25.78 0.001
TAS, mmol/l 0.8±0.1 0.9±0.1 0.8±0.1 0.7±0.1 0.8±0.1 0.843 0.508
GPX, U/g Hb 348±13 365±17 360±10 349±16 373±22 0.38 0.822
AGE-Fl/Alb, AU/g 0.33±0.03 0.44±0.01* 0.43±0.03 0.42±0.02 0.39±0.02 3.91 0.012
CTRL – sham operated control rats; UUO – unilateral ureteral obstruction; P – placebo; E – Phlogenzym; ABR – losartan; COMB –
combined treatment with E + ABR; ANOVA – one-way analysis of variance; K-W – Kruskal-Wallis test (in italics); wt – weight; SBP –
systolic blood pressure; CL: contralateral; crea: creatinine; MDA: malondialdehyde; AU: arbitrary units; TAS: total antioxidant status;
GPX – glutathione peroxidase activity; U – units; Hb – hemoglobin; AGE-Fl – advanced glycation end products specific fluorescence; Alb –
albumin; *p < 0.05 vs. CTRL; **p < 0.01 vs. CTRL; + – p < 0.05 vs. UUO-P; ++ – p < 0.01 vs. UUO-P.
interstitial fibrosis. Thus, a predominant excretion of
AGE-modified peptides is anticipated. Their enhanced
filtration load might also contribute to the damage of
tubule cells with subsequent development of tubulo-
interstitial fibrosis.
Role of enhanced oxidative stress in pathogenesis
of UUO (Table). Fourteen days after the induction of
UUO oxidative stress was systemically enhanced, as re-
flected by increased MDA and lipofuscin levels. CML
is considered as integrative biomarker of the cumula-
tive protein damage induced by glycoxidation [26].
Much faster accumulation of CML than that of fluo-
rescent AGEs, and high correlation between CML and
MDA (r = 0.599, p < 0.05), or CML and LF concentra-
tions (r = 0.556, p < 0.05), support the role of the oxida-
tive stress in CML formation. Since the total antioxi-
dant status and GPX activity were not altered, the en-
hanced oxidative stress seemed to result from overpro-
duction of ROS, not caused by a compromised
antioxidant defense. Shortly (12 h) after the onset of
UUO heme oxygenase-1 activity increases, with a time
dependent decline within the next 7 days [5]. It might
not be excluded that during the early phase of UUO,
enhanced production of ROS induces antioxidant en-
zyme activity, which returns to normal values, or even
decreases, later.
Although the function of the CL kidney was only
slightly altered, both plasma AGE-specific fluoresce, as
well as CML levels correlated highly with those of se-
rum creatinine (r = 0.560, p < 0.05, and r = 0.760, p <
< 0.001, respectively), indicating the important role of
the kidney in their removal, and the role of oxidative
stress in the impairment of renal function.
Effects of the treatment. We compared the estab-
lished beneficial effects of the administration of losar-
tan with the potential beneficial action of Phlogenzym
and their combination on the function of the CL kidney,
from the point of interference with AGEs and oxidative
status, since: 1) inhibitors of converting enzyme and
ARBs ameliorate the alterations induced by UUO [27];
2) the experimental and clinical data suggest that ARBs
may attenuate oxidative stress and formation of AGEs
[13, 28, 29]; 3) proteolytic enzymes antagonize the
AGE-induced toxicity in various renal cell cultures [15,
124
SEBEKOVA K.JR. ET AL.
15
10
0
++
+
**
Protein/DNA glomeruli Cortex collagen area
0,4
0,2
0,1
0
0,3
[%
]
UUO-E; UUO-ARB; UUO-COMBCTRL; UUO-P;
a
**,++
*,++
**
++
[m
g
/m
g]
5
b
Fig. 1. Effects of UUO, and treatment with
Phlogenzym, losartan, and their combina-
tion on contralateral kidney: a – protein to
DNA ratio in isolated glomeruli; b – renal
cortex collagen content. CTRL – sham
operated controls; UUO – unilateral ureteral
obstruction; P – placebo; E – Phlogenzym;
ARB – losartan; COMB – combined treat-
ment with E + ABR; *p < 0.05 vs. CTRL; **p
< 0.01 vs. CTRL; + – p < 0.05 vs. UUO-P;
++ – p < 0.01 vs. UUO-P
4
2
1
0
3
5
**
++
*,++
**
*
UUO-E; UUO-ARB; UUO-COMBCTRL; UUO-P;
4
2
1
0
3
5
S-CML
[U
/m
m
o
l
cr
ea
]
[U
/g
A
lb
]
U-CML
a b
Fig. 2. Plasma levels and urinary excretion
of Ne-(carboxymethyl)lysine (CML): a – S-
CML; b – U-CML. CTRL – sham operated
controls; UUO – unilateral ureteral obst-
ruction; P – placebo; E – Phlogenzym;
ARB– losartan; COMB – combined treat-
ment with E + ABR; Alb – albumin; crea –
creatinine
16], and in models of progressive renal diseases ad-
ministration of Phlogenzym exerted beneficial effects
of on renal function and morphology [17, 18].
Contralateral kidney (Table). Administration of
Phlogenzym, losartan or their combination to UUO rats
resulted in comparable improvement of the CL kidney
function, although significant decline in plasma creati-
nine concentration was reached only in UUO-E group.
Urea accumulation was ameliorated in UUO-E and
UUO-COMB groups. Treatment did not affect protein-
uria, the body weight, CL kidney weight, or kidney/bo-
dy weight ratio. All treatment modalities ameliorated
renal cortex collagen accumulation (Fig. 1, b). In all tre-
ated groups glomerular protein/DNA ratio was lower
than in the UUO-P rats, reaching significance in the
UUO-E and UUO-ARB groups (Fig. 1, a). Glomerular
protein/DNA ratio correlated with plasma CML level
(r = 0.458, p < 0.01). These data correspond with our
previous findings in in vitro studies. In LLC-PK1 cells
trypsin inhibited the AGE-induced cell hypertrophy,
overexpression of TGF-b1 mRNA, total TGF-b1 pro-
tein, and increased AGE accumulation [15, 16]. The
above mentioned AGE-induced effects, as well as acti-
vation of protein kinase C and enhanced fibronectin
synthesis were diminished also by co-incubation with
losartan in IHKECs and LLC-PK1 cells [12]. Thus, in-
terference of both, proteases and ARB with TGF-b1,
may in vivo result in attenuation hypertrophy, and of
collagen accumulation.
Oxidative status (Table) and AGEs. Phlogenzym
significantly ameliorated the rise in MDA. Lipofuscin
levels remained elevated under treatment with ARB,
pointing to a shift of lipid peroxidation towards secon-
dary products. The antioxidant defense (TAS and GPX
activity) was not influenced by any of the interventions.
AGE-specific fluorescence was not influenced signifi-
cantly by either treatment. Plasma CML levels were
ameliorated by the administration of Phlogenzym alone
or in combination with ABR. Urinary excretion of
CML remained elevated in the UUO-ARB group (Fig.
2). Changes in CML levels observed under the treat-
ment were not on the account of blood pressure, plasma
albumin, or glucose concentrations. Potential involve-
ment of oxidative events is supported by tight relation-
ship between CML and MDA (r = 0.519, p < 0.001), or
CML and LF concentrations (r = 0.755, p < 0.001).
Thus, partial persistence of enhanced oxidative
stress under treatment with ARB was further reflected
by elevated CML levels, despite of only a mild rise in
plasma creatinine, and substantial increase in urinary
CML excretion. At first glance this data are contra-
dictory to our previous observation, in which the 12-
weeks-long administration of losartan to subtotally
nephrectomized rats completely prevented the rise in
plasma AGE levels [13]. However, in both studies
losartan significantly increased urinary AGE excretion.
We suppose that in spite of enhanced renal excretion
longer time is needed to normalize the elevated circu-
lating AGE levels. Moreover, it is equivocal whether
the sub-antihypertensive dose of losartan administered
in our study is sufficient to block the oxidative stress
induced by Ang II. In the rat model of congestive heart
failure, an increase in antioxidant defense and a decline
in oxidative stress was achieved after administration of
a 100-fold higher dose of losartan [29]. Losartan
effectively prevented glomerular hypertrophy and col-
lagen accumulation, despite persistent oxidative stress
and elevated AGE levels. ARBs were capable to reduce
the expression of RAGE in human endothelial cells,
and to modify the AGE-RAGE interaction by suppres-
sion of RAGE expression in the type 2 diabetic KK/Ta
mice [11, 30]. We suppose that suppression of RAGE
under ARB treatment may to measurable extent prevent
progressive renal damage even under the persisting oxi-
dative stress.
Phlogenzym attenuated accumulation of AGEs and
lipid peroxidation products. CML adducts are one of
the most relevant ligands for RAGE and mediate NF-
kB pathways, resulting in intracellular generation of
ROS [9, 31]. In in vitro studies proteases could in-
activate the extracellular domain of the RAGE, thus
interfere directly with production of ROS, decreasing
formation of AGEs and lipid peroxidation products [15,
16]. However, in Phlogenzym, rhutosid is added as
antioxidant to stabilize trypsin and bromelain. In vitro,
antioxidants ameliorate the toxic effects induced by
AGEs [28]. According to our knowledge no data are
available on the antioxidant/anti-AGE effects of rhuto-
sid. However, water-soluble rutin derivative suppres-
sed in vitro glycation in tissue proteins [32]. Thus, the
observed mechanisms of beneficial effects of Phlogen-
zym are to be interpreted with caution.
125
RAT UUO MODEL: EFFECTS OF PHLOGENZYM AND LOSARTAN
Combined treatment showed additive effects and
partially prevented the changes under ARB treatment,
suggesting different mechanisms of the beneficial
effects on CL kidney function of enzymes or ARBs.
Conclusions. Our study confirms the role of syste-
mically enhanced oxidative stress in UUO, as reflected
by increased plasma malondialdehyde, lipofuscin,
CML and fluorescent AGE levels. Enhanced oxidative
stress may be involved not only in the development of
tubulointerstitial fibrosis of the ligated kidney, but also
in impairment of the CL kidney. Suppression of oxi-
dative stress and glycoxidation might therefore be of
clinical relevance in retardation of the progression of
renal disease.
Acknowledgements. Support from the Verein zur
Bekampfung der Hochdruck- und Nierenkrankheiten,
Wurzburg e. V., Germany, and an excellent help of
Mr. Andre Klassen in preparation of the manuscript is
acknowledged.
Ê. Äæ. Øå áå êî âà, Ï. Áëà æè ÷åê, Ä. Ñè ðî âà, Ø. Ãàë áàâ³,
À. Õåé äëàíä, Ê. Øå áå êî âà
Îêñè äà òèâ íèé ñòðåñ, ê³íöåâ³ ïðî äóê òè ãë³êàö³¿ òà çà ëèø êî âå
ôóíêö³îíó âàí íÿ íè ðêè íà ìî äåë³ ùóð³â ç óí³ëà òå ðàëü íîþ
îá ñòðóêö³ºþ ñå ÷î âî äó: åôåê òè ôëî ãåí çè ìó òà ëî ñàð òà íó
Ðå çþ ìå
Ìåòà. Îêñè äà òèâ íèé ñòðåñ â³ä³ãðຠçíà÷ íó ðîëü ó ïà òî ãå íåç³
îá ñòðóêö³¿ ñå ÷î âî äó. Ìåòà ðî áî òè ïî ëÿ ãà ëà ó âèâ ÷åíí³ ïà ðà -
ìåòð³â îêñè äà òèâ íî ãî ñòà òó ñó, îö³íþ âàíí³ ð³âíÿ ê³íöå âèõ ïðî -
äóêò³â ãë³êàö³¿ ³ ôóíêö³îíó âàí íÿ êîí òðà ëà òå ðàëü íî¿ íè ðêè íà
ìî äåë³ ùóð³â ç óí³ëà òå ðàëü íîþ îá ñòðóêö³ºþ ñå ÷î âî äó (ÓÎÑ).
Ìå òî äè. Íà ìî äåë³ ÓÎÑ äîñë³äæó âà ëè åôåê òè ôëî ãåí çè ìó
(12 ìã â äåíü îðàëü íî) ³ ëî ñàð òà íó (20 ìã/ë ó ïèòí³é âîä³), à òà -
êîæ ¿õíüî¿ êîìá³íàö³¿. Ðå çóëü òà òè. Ó ùóð³â ç ÓÎÑ, ÿê³ îò ðè -
ìó âà ëè ïëà öå áî, ð³âåíü íà êî ïè ÷åí íÿ ê³íöå âèõ ïðî äóêò³â ãë³êàö³¿
òà ìà ëîíä³àëü äåã³äó âè ÿ âèâ ñÿ âè ùèì, í³æ ó íå ñïðà âæíüîîïå -
ðî âà íèõ êîí òðîëü íèõ ùóð³â. Ôóíêö³îíó âàí íÿ êîí òðà ëà òå ðàëü -
íî¿ íè ðêè íå çíà÷ íî ïîã³ðøè ëî ñÿ, êîí öåí òðàö³ÿ êî ëà ãå íó ³ ñï³â-
â³äíî øåí íÿ âì³ñòó á³ëîê/äåç îêñè ðè áî íóê ëå¿ íî âà êèñ ëî òà (P/
DNA) ó êëó áî÷ êó íè ðêè ï³äâè ùåí³. Îáðîá êà äîñë³äæó âà íè ìè
ë³êà ðñüêè ìè çà ñî áà ìè çà ïîá³ãàëà çá³ëüøåí íþ âì³ñòó êî ëà ãå íó,
çðîñ òàí íþ ïî êàç íè êà ñï³ââ³äíî øåí íÿ P/DNA òà ïî êðà ùóâàëà
ôóíêö³îíó âàí íÿ êî ëà òå ðàëü íî¿ íè ðêè. Ôëî ãåí çèì ñïðèÿâ ï³äâè -
ùåí íþ ð³âíÿ ïå ðå êèñ íî ãî îêèñ íåí íÿ ë³ï³ä³â òà ê³íöå âèõ ïðî -
äóêò³â ãë³êàö³¿. Âèñ íîâ êè. Ó ìî äåë³ ÓÎÑ ñèñ òå ìà òè÷ íå çá³ëü-
øåí íÿ îêñè äà òèâ íî ãî ñòðå ñó ìîæå â³ä³ãðà âà òè âàæ ëè âó ðîëü
ó ðîç âèòêó òó áó ëî³íòåð ñòèö³éíî ãî ô³áðî çó ³ ïî ðó øåíí³ ôóíê-
ö³îíó âàí íÿ êîí òðà ëà òå ðàëü íî¿ íè ðêè. Ñóï ðåñ³ÿ îêñè äà òèâ íî ãî
ñòðå ñó òà áëî êó âàí íÿ ðå öåï òî ðà àíã³îò åí çè íó-1 ìîæóòü ïî -
ñëàá ëþâàòè ïðî ãðåñ³þ îá ñòðóê òèâ íî¿ óðî ïàò³¿.
Êëþ ÷îâ³ ñëî âà: îá ñòðóêö³ÿ ñå ÷î âî äó, îêñè äà òèâ íèé ñòðåñ,
ìà ëîíä³àëü äåã³ä, êî ëà ãåí.
Ê. Äæ. Øå áå êî âà, Ï. Áëà æè ÷åê, Ä. Ñûðî âà, Ø. Ãàë áàâè,
À. Õåé äëàíä, Ê. Øå áå êî âà
Îêñè äà òèâ íûé ñòðåññ, êî íå÷ íûå ïðî äóê òû ãëè êà öèè
è îñòà òî÷ íîå ôóíê öè î íè ðî âà íèå ïî ÷êè íà ìî äå ëè êðûñ
ñ îá ñòðóêöèåé ìî ÷å òî÷ íè êà: ýô ôåêòû ôëî ãåí çèìà è ëî ñàð òàíà
Ðå çþ ìå
Öåëü. Îêñè äà òèâíûé ñòðåññ èã ðà åò çíà ÷è òåëü íóþ ðîëü â ïà -
òî ãå íå çå îá ñòðóêöèè ìî ÷å òî÷ íè êà. Öåëü ðàáî òû ñî ñòî ÿ ëà â
èçó÷å íèè ïà ðà ìåòðîâ îêñè äà òèâ íî ãî ñòà òóñà, îöåíêå óðîâíÿ
êî íå÷ íûõ ïðî äóêòîâ ãëè êà öèè è ôóíê öèîíèðîâàíèÿ êîí òðà ëà -
òå ðàëü íîé ïî ÷êè íà ìî äåëè êðûñ ñ óíè ëà òå ðàëü íîé îá ñòðóê öè -
åé ìî ÷å òî÷ íè êà (ÓÎÌ). Ìå òî äè. Íà ìî äåëè ÓÎÌ èñ ñëå äî âà ëè
ýô ôåêòû ôëî ãåí çèìà (12 ìã â äåíü îðàëü íî) è ëî ñàð òàíà
(20 ìã/ë â ïèòü å âîé âîäå), à òàêæå èõ êîì áèíà öèè. Ðå çóëü òà -
òû. Ó êðûñ ñ ÓÎÌ, ïîëó÷àâøèõ ïëà öå áî, óðîâåíü êî íå÷ íûõ ïðî -
äóêòîâ ãëè êà öèè è ìà ëîí äè àëü äå ãèäà îêà çàë ñÿ âûøå, ÷åì ó
ëîæíîîîïå ðî âàííûõ êîí òðîëü íûõ êðûñ. Ôóí êöè î íè ðî âà íèå
êîí òðà ëà òå ðàëü íîé ïî ÷êè íå çíà ÷è òåëü íî óõóä øè ëîñü, êîí öåí -
òðà öèÿ êîë ëà ãå íà è ñî îò íî øå íèå ñî äåð æà íèÿ áåëîê/äåç îêñè -
ðè áî íóê ëåè íî âàÿ êèñ ëî òà (P/DNA) â êëó áî÷ êå ïî ÷êè ïî âû ñè-
ëèñü. Îáðà áîò êà èñ ñëå äó å ìû ìè ëå êà ðñòâåí íû ìè ñðåä ñòà âà ìè
ïðåä îò âðà ùàëà óâå ëè ÷å íèå ñî äåð æà íèÿ êîë ëà ãåíà, ïî êà çà òå ëÿ
ñî îò íî øå íèÿ P/DNA è óëó÷ øàëà ôóíê öè î íè ðî âà íèå êî ëà òå -
ðàëü íîé ïî ÷êè. Ôëî ãåí çèì ñïî ñî áñòâî âàë âîç ðàñ òà íèþ óðîâíÿ
ïå ðå êèñ íî ãî îêèñ ëå íèÿ ëè ïè äîâ è êî íå÷íûõ ïðî äóêòîâ ãëè êà-
öèè. Âû âî äû.  ìî äåëè ÓÎÌ ñèñ òå ìà òè ÷åñêîå óâå ëè ÷å íèå îê-
ñè äà òèâ íî ãî ñòðåññà ìî æåò áûòü ïðè ÷è íîé ðàç âèòèÿ òó áó -
ëî èí òåð ñòè öèî ííî ãî ôèá ðî çà è íà ðó øå íèÿ ôóíê öè î íè ðî âà íèÿ
êîí òðà ëà òå ðàëü íîé ïî ÷êè. Ñóï ðåñ ñèÿ îêñè äà òèâ íî ãî ñòðåññà
è áëî êè ðî âà íèå ðå öåï òî ðà àí ãè î òåí çè íà-1 ìîæãóò îñëàá ëÿòü
ïðî ãðå ññèþ îá ñòðóê òèâ íîé óðî ïàòèè.
Êëþ ÷åâûå ñëî âà: îá ñòðóê öèÿ ìî ÷å òî÷ íè êà, îêñè äà òèâíûé
ñòðåññ, ìà ëîí äè àëü äåãèä, êî ëëà ãåí.
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UDC 616.61-008.6
Received 10.01.10
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