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Effects of Ramipril in Nondiabetic Nephropathy: Improved Parameters of Oxidatives Stress and Potential Modulation of Advanced Glycation End Products

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Effects of Ramipril in Nondiabetic Nephropathy: Improved Parameters of Oxidatives Stress and Potential Modulation of Advanced Glycation End Products Journal of Human Hypertension (2003) 17, 265–270 & 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00 www.nature.com/jhh ORIGINAL ARITICLE Effects of ramipril in nondiabetic nephropathy: improved parameters of oxidatives stress and potential modulation of advanced glycation end products KSˇ ebekova´1, K Gazdı´kova´1, D Syrova´2, P Blazˇı´cˇek2, R Schinzel3, A Heidland3, V Spustova´1 and R Dzu´ rik 1Institute of Preventive and Clinical Medicine, Bratislava, Slovakia; 2Military Hospital, Bratislava, Slovakia; 3University Wuerzburg, Germany Enhanced oxidative stress is involved in the progres- patients on conventional therapy did not differ signifi- sion of renal disease. Since angiotensin converting cantly from the ramipril group, except for higher Hcy enzyme inhibitors (ACEI) have been shown to improve levels in the latter. Administration of ramipril resulted in the antioxidative defence, we investigated, in patients a drop in blood pressure and proteinuria, while creati- with nondiabetic nephropathy, the short-term effect of nine clearance remained the same. The fluorescent the ACEI ramipril on parameters of oxidative stress, AGEs exhibited a mild but significant decline, yet CML such as advanced glycation end products (AGEs), concentration was unchanged. The AOPP and malon- advanced oxidation protein products (AOPPs), homo- dialdehyde concentrations decreased, while a small rise cysteine (Hcy), and lipid peroxidation products. Ramipril in neopterin levels was evident after treatment. The (2.5–5.0 mg/day) was administered to 12 newly diag- mentioned parameters were not affected significantly in nosed patients for 2 months and data compared with a the conventionally treated patients. Evidence that rami- patient group under conventional therapy (diuretic/ pril administration results in a mild decline of fluores- b-blockers) and with age- and sex-matched healthy cent AGEs is herein presented for the first time. The subjects (CTRL). Patients had mild to moderate renal underlying mechanism may be decreased oxidative insufficiency and showed, in the plasma, higher fluor- stress, as indicated by a decline in AOPPs and escent AGE and carboxymethyllysine (CML) levels, as malondialdehyde. well as elevated concentrations of AOPPs, lipofuscin Journal of Human Hypertension (2003) 17, 265–270. and Hcy when compared with CTRL. Basal data of the doi:10.1038/sj.jhh.1001541 Keywords: nondiabetic nephropathy; fluorescent AGEs; carboxymethyllysine; advanced oxidation protein products (AOPPs); malondialdehyde; ramipril Introduction rise is attributed to enhanced formation, because of carbonyl and oxidative stress.7,8 AGEs exert their Chronic renal insufficiency (CRI) is associated with toxicity both directlyFby alerting the structure/ an enhanced oxidative stress, which is assumed to function of plasma/tissue proteins9Fand indirec- accelerate the progression of renal and cardiovas- F 1,2 tly after their binding to the specific cell surface cular disease. Among the numerous uremic receptorFincluding RAGE.10 This interaction leads toxins, three different compounds show an associa- to the production of reactive oxygen species, which tion with enhanced oxidative stress. (1) Advanced may in turn accelerate formation of AGEs and lipid glycation end products (AGEs) accumulate in the peroxidation products. (2) Homocysteine (Hcy)Fan organism during experimental and clinical human independent risk factor of cardiovascular diseaseF kidney disease in proportion to the decline in renal 11 3–6 accumulates in circulation of patients with CRI. function. Besides decreased renal removal, their Its auto-oxidation results in the production of reactive oxygen radicals,12 which may contribute to the oxidative stress in the renal disease. (3) Correspondence: Dr K Sˇ ebekova´, Institute of Preventive and Advanced oxidation protein products (AOPPs)F Clinical Medicine, Limbova´ 14, 833 01 Bratislava, Slovakia. F E-mail: [email protected] markers of in vivo protein oxidation accumulate Received 29 May 2002; revised 19 December 2002; accepted 28 in CRI patients consistently, as a consequence December 2002 of impaired renal function.13 They are supposed Ramipril affects AGEs and AOPPs KSˇebekova´ et al 266 to result predominantly from the myeloperoxidase Patients and methods reaction. It still remains questionable whether Patients enhanced oxidative stress may directly potentiate their formation. A high correlation between A total of 12 newly diagnosed individuals with plasma AOPPs and pentosidineFa chemically nondiabetic kidney disease (tubulointerstitial ne- defined AGEFwas revealed.13 phritis, n ¼ 8; glomerulonephritis, n ¼ 2; polycystic Angiotensin-converting enzyme inhibitors (ACEI), kidney disease, n ¼ 2) and impaired renal function alongside their nonhaemodynamic actions, may (serum creatinine 4110 mmol/l or creatinine clear- also improve the defence against oxidative stress. ance o60 ml/min) were administered the ACEI On the one hand, amelioration of the oxidative ramipril (Tritace, Aventis, France) at a dose of 2.5– stress result from the lowered plasma and tissue 5 mg/day over 2 months. Patients’ data were com- angiotensin II (AT II) concentrations. On the other pared to two control groups: (1) seven patients with hand, ACEI containing a sulphydryl moiety in their non-diabetic kidney disease (tubulointerstitial ne- molecule act as free radical and oxidant scavengers, phritis, n ¼ 6; tubulopathy, n ¼ 1) with mild to while lipid peroxidation is inhibited by both moderate renal insufficiency (serum creatinine sulphydryl- and non-sulphydryl-containing ACEI.14 4110 mmol/l or creatinine clearanceo60 ml/min) In in vitro studies, ACEI and AT II type 1 receptor on a long-term antihypertensive treatment with antagonists lower formation of AGEs by inhibition of diuretics and/or b-receptor blockers; and (2) 10 various oxidative steps, as well as the production of age- and sex-matched healthy controls (CTRL), reactive carbonyl species.15 Moreover, in various who were free of any medication 3 months prior to models of experimental renal disease, an attenua- the investigation. To control for the potential tion of oxidative stress following ACEI or AT II seasonal variation in the investigated data: (1) the receptor 1 antagonist (R1A) administration has been patients were recruited into the study within 1 demonstrated.16–19 month, (2) they were instructed not to change their The above-mentioned lines of evidence prompted eating behaviour during the study, (3) blood samples us to investigate whether the protective actions of were taken from patients on conventional therapy ACEI might also be mediated in humans, at least also after the 2-month period for determination of in part, by modulation of the oxidative status. the studied parameters. Group characteristics are Thus, we followed the plasma levels of AGEs, given in Table 1. AOPPs, Hcy and parameters reflecting lipid perox- The study was carried out in accordance with the idation in patients with nondiabetic nephro- Declaration of Helsinki and reviewed and approved pathy during short-term administration of the ACEI by the Institutional Ethics Board. All participants ramipril. signed a written consent. Table 1 Clinical and biochemical data of the investigated groups of the healthy controls and the patients with nondiabetic nephropathies on the conventional treatment (diuretic/b-blocker) or ramipril before and after 2 months CTRL n=10 Conv. basal n=7 Conv. 2M Ram basal n=12 Ram 2M Gender 6F/4M 5F/2M 4F/8M Age (years) 56.0 7 7.5 63.7 7 11.4 62.7 7 13.4 SBP (mm Hg) 136.0 7 11.0 115.0 7 17.1c 116.4 7 15.7c 161.7 7 14.1c 133.8 7 15.7** DBP (mm Hg) 85.5 7 7.6 71.4 7 9.5c 7.52 7 7.0c 97.1 7 4.2c 83.3 7 5.9** Creatinine (mmol/l) 82.7 7 17.6 182.8 7 166.8 175.3 7 168.2 170.9 7 72.7c 168.9 7 68.8c Cl Crea (ml/s) 1.69 7 0.38 0.75 7 0.21c 0.75 7 0.19c 0.72 7 0.52c 0.76 7 0.24c Cystatin C (mg/dl) 0.84 7 0.16 1.42 7 0.85a 1.38 7 0.88a 1.68 7 0.83c 1.65 7 0.80c Glucose (mmol/l) 4.81 7 1.09 4.12 7 0.55 4.54 7 0.72 4.65 7 0.70 4.29 7 0.82 AGE-Fl (AU) 271.0 7 68.1 452.3 7 198.6c 443.7 7 197.1b 455.9 7 137.7c 405.8 7 92.4c,* CML (ng/ml) 528.78 7 229.9 965.8 7 260.4c 1006.0 7 260.4c 888.7 7 456.5c 893.7 7 445.9c AOPPs (mmol/l) 25.96 7 9.85 52.17 7 19.61c 48.28 7 15.7a 53.73 7 21.51c 39.04 7 14.2c,* Neopterin (ng/ml) 1.7 7 0.3 4.3 7 5.3 4.3 7 5.3 4.1 7 1.7c 5.4 7 3.2c MDA (mmol/l) 5.6 7 1.7 5.5 7 2.4 5.0 7 2.3 5.5 7 2.1 3.8 7 1.3**,c Lipofuscin (AU) 24.5 7 2.7 32.3 7 11.6a 31.1 7 13.3 30.1 7 4.2c 30.2 7 3.6c Hcy (mmol/l) 11.7 7 2.6 13.0 7 0.9 13.6 7 1.0 17.6 7 1.4c 18.1 7 1.2c CTRL: healthy controls; Conv.: conventional treatment; Ram: group treated with ramipril; 2M: values after 2 months treatment; SBP: systolic blood pressure; DBP: diastolic blood pressure; Cl Crea: creatinine clearance; AGE-Fl: fluorescent advanced glycation end products; CML: carboxymethyllysine; AOPPs: advanced oxidation protein products; MDA: malondialdehyde; AU: arbitrary units. aPo0.05 vs CTRL. bPo0.02 vs CTRL. cPo0.01 vs CTRL. *Po0.05 vs 0. **Po0.01 vs 0. Journal of Human Hypertension Ramipril affects AGEs and AOPPs KSˇebekova´ et al 267 Analytical methods Table 2 Frequency of urinary findings in the investigated groups of the healthy controls and the patients with nondiabetic Venous blood was collected into K2EDTA and nephropathies on the conventional treatment (diuretic/b-blocker) Li-heparin tubes, centrifuged within 1 h after collec- or ramipril before and after 2 months tion and stored at À701C.
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