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Effect of Eplerenone, a Selective Aldosterone Blocker, on the Development of Diabetic Nephropathy in Type 2 Diabetic Rats
Jae Hee Ahn, Ho Cheol Hong, Myong Jin Cho, Yoon Jung Kim, Hae Yoon Choi, Chai Ryoung Eun, Sae Jeong Yang, Hye Jin Yoo, Hee Young Kim, Ji A Seo, Sin Gon Kim, Kyung Mook Choi, Sei Hyun Baik, Dong Seop Choi, Nan Hee Kim
Diabetes Metab J. 2012;36(2):128-135.   Published online April 17, 2012
DOI: https://doi.org/10.4093/dmj.2012.36.2.128
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  • 38 Download
  • 9 Crossref
AbstractAbstract PDFPubReader   
Background

Aldosterone antagonists are reported to have beneficial effects on diabetic nephropathy by effective blocking of the renin-angiotensin-aldosterone system. We investigated the renoprotective effect of the selective aldosterone receptor blocker eplerenone, the angiotensin converting enzyme inhibitor lisinopril, and combined eplerenone and lisinopril treatment in type 2 diabetic rats.

Methods

Animals were divided into six groups as follows: Otsuka Long-Evans Tokushima Fatty (OLETF) rat control, OLETF rats treated with a low dose of eplerenone (50 mg/kg/day), OLETF rats treated with a high dose of eplerenone (200 mg/kg/day), OLETF rats treated with lisinopril (10 mg/kg/day), OLETF rats treated with a combination of both drugs (eplerenone 200 mg/kg/day and lisinopril 10 mg/kg/day), and obese non-diabetic Long-Evans Tokushima Otsuka rats for 26 weeks.

Results

Urinary albumin excretion was significantly lower in the lisinopril group, but not in the eplerenone group. Urinary albumin excretion was decreased in the combination group than in the lisinopril group. Glomerulosclerosis and renal expression of type I and type IV collagen, plasminogen activator inhibitor-1, transforming growth factor-β1, connective tissue growth factor, and fibronectin mRNA were markedly decreased in the lisinopril, eplerenone, and combination groups.

Conclusion

Eplerenone and lisinopril combination showed additional benefits on type 2 diabetic nephropathy compared to monotherapy of each drug.

Citations

Citations to this article as recorded by  
  • Up-Date on Diabetic Nephropathy
    Maria Chiara Pelle, Michele Provenzano, Marco Busutti, Clara Valentina Porcu, Isabella Zaffina, Lucia Stanga, Franco Arturi
    Life.2022; 12(8): 1202.     CrossRef
  • The role of free radical oxidation in the kidneys in the nephroprotective action of eplerenone, a mineralocorticoid receptor antagonist, in experimental diabetes mellitus
    A. Yu. Zharikov, S. O. Filinova, O. N. Mazko, O. G. Makarova, I. P. Bobrov, V. M. Bryukhanov
    Bulletin of Siberian Medicine.2021; 20(2): 29.     CrossRef
  • Effect of Mineralocorticoid Receptor Antagonism and ACE Inhibition on Angiotensin Profiles in Diabetic Kidney Disease: An Exploratory Study
    Johannes J. Kovarik, Christopher C. Kaltenecker, Oliver Domenig, Marlies Antlanger, Marko Poglitsch, Chantal Kopecky, Marcus D. Säemann
    Diabetes Therapy.2021; 12(9): 2485.     CrossRef
  • Diabetic nephropathy: An update on pathogenesis and drug development
    Vikram Rao A/L B Vasanth Rao, Sean Hong Tan, Mayuren Candasamy, Subrat Kumar Bhattamisra
    Diabetes & Metabolic Syndrome: Clinical Research & Reviews.2019; 13(1): 754.     CrossRef
  • Effects of mineralocorticoid receptor antagonists on the progression of diabetic nephropathy
    Li‐Jing Sun, Yan‐Ni Sun, Jian‐Ping Shan, Geng‐Ru Jiang
    Journal of Diabetes Investigation.2017; 8(4): 609.     CrossRef
  • New agents modulating the renin-angiotensin-aldosterone system—Will there be a new therapeutic option?
    Anna Gromotowicz-Poplawska, Piotr Szoka, Patrycjusz Kolodziejczyk, Karol Kramkowski, Marzena Wojewodzka-Zelezniakowicz, Ewa Chabielska
    Experimental Biology and Medicine.2016; 241(17): 1888.     CrossRef
  • Crosstalk between peroxisome proliferator-activated receptor-γ and mineralcorticoid receptor in TNF-α activated renal tubular cell
    Jing Xiao, Weijun Chen, Yijun Lu, Xiaoli Zhang, Chensheng Fu, Zhenwen Yan, Zhenxing Zhang, Zhibin Ye
    Inflammation Research.2015; 64(8): 603.     CrossRef
  • Eplerenone reduces arterial thrombosis in diabetic rats
    Agnieszka Zakrzeska, Anna Gromotowicz-Popławska, Janusz Szemraj, Piotr Szoka, Wioleta Kisiel, Tomasz Purta, Irena Kasacka, Ewa Chabielska
    Journal of the Renin-Angiotensin-Aldosterone System.2015; 16(4): 1085.     CrossRef
  • Pharmacological modulation of fibrinolytic response – In vivo and in vitro studies
    Karol Kramkowski, Agnieszka Leszczynska, Wlodzimierz Buczko
    Pharmacological Reports.2015; 67(4): 695.     CrossRef
Effect of Red Ginseng Extract on Lipid Peroxidation in Streptozotocin-induced Diabetic Rats.
Hee Jong Jin, Sung Hee Ihm, Ja Hei Ihm
Korean Diabetes J. 2001;25(5):374-383.   Published online October 1, 2001
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AbstractAbstract PDF
BACKGROUND
Diabetes mellitus is postulated to be associated with increased oxidative stress and lipid peroxidation which may contribute to vascular complications. Recently ginseng (Panax) has been shown to have an antioxidant effect by enhancing nitric oxide synthesis in endothelial cells and by directly scavenging hydroxyl radicals. It is unknown whether ginseng might act as an antioxidant against lipid peroxidation in diabetes. METHODS: We studied the in vitro effect of red ginseng extract on lipid peroxidation employing phospholipid liposome and low-density lipoprotein (LDL) as a model system. To investigate the in vivo effect on lipid peroxidation in diabetes, we administered red ginseng extract (1 g/L in drinking water) to streptozotocin (STZ)- induced diabetic rats for 12 weeks and measured lipid peroxidation products in plasma, liver, kidneys and heart. RESULTS: The Fe(3+)- or Cu(2+)- mediated lipid peroxidation in phospholipid liposome and LDL, measured by the concentration of TBARS, was inhibited in the presence of red ginseng extract. MDA level in plasma measured by HPLC was higher in STZ-induced diabetic rats than in control rats. Plasma MDA level was lower by 41% in red ginseng-treated diabetic rats than in untreated diabetic rats. Tissue MDA levels measured by TBA method in liver, kidneys and heart were higher in STZ-induced diabetic rats than in control rats. In red ginseng-treated diabetic rats tissue MDA levels were lower by 14~30% than in untreated diabetic rats. CONCLUSION: We observed that red ginseng extract has an effect in inhibiting lipid peroxidation both in vitro and in STZ-induced diabetic rats. These results suggest that red ginseng might have a beneficial effect in diabetes as an antioxidant against lipid peroxidation and diabetic vascular complications.
Effect of Heat Shock on the Vascular Reactivity in Diabetic Rat Aorta.
Seong Mo Koo, Soon Hee Lee, Jung Hun Han, Gi Young Jeong, In Kyum Kim, Jung Guk Kim, Sung Woo Ha, Bo Wan Kim
Korean Diabetes J. 2001;25(5):343-353.   Published online October 1, 2001
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  • 18 Download
AbstractAbstract PDF
BACKGROUND
Heat shock has been known to change cellular response to noxious stimuli by inducing heat shock proteins (HSP). HSP are expressed in many tissues, and increased expression of some HSP enhances the survival of cells exposed to oxidative stress. Recently, Some HSP are known to associate with vascular reactivity. Under diabetic conditions, there is abnormal vascular reactivity to relaxing or contracting factors. Abnormal vascular response to some stimuli is an important role in the development of diabetic complications. However, the effects of heat shock on the vascular reactivity in diabetic condition is unclear. Therefore, we investigated effects of heat shock on the vascular reactivity in isolated aorta of streptozotocin-induced diabetic rats. METHODS: After mounced in organ bath, aortic ring preparations were exposed to 42 for 45 minutes followed by being subjected to contraction and relaxation in 4 hours. Tissues were frozen for measurement of HSP 70 and phosphorylation of myosin light chain after functional study. RESULTS: Heat shock not only increased expression of HSP70 in rat aorta but also augmented contraction to KCl and phenylephrine in the aorta of control and diabetic rats (p<0.05). Relaxation responses to acetylcholine (ACh) were not changed in the aorta of control rats with and without heat shock for 45 minutes. However, heat shock for 45 minutes decreased relaxative responses to ACh in the aorta of diabetic rats compared to those in the aorta of control rats. CONCLUSION: This result suggests that heat shock increases vascular contractility in the aorta of diabetic and control rats through the induction of HSP70 while heat shock seems to decrease relaxative response in the aorta of diabetic ratscompared to control rats (p<0.05). Whether heat shock impaired relaxative response in the aorta of diabetic rats deserves additional studies.
Proliferative Ability of Aortic Smooth Muscle Cells and Lipid Peroxidation of Red Blood Cell Membrane in Diabetic Rats.
Sae Young Park, Hyung Joon Yoo, Kyun Soo Kim, Hyun Kyu Kim, Doo Man Kim, Jae Myung Yoo, Sung Hee Ihm, Moon Gi Choi, Sung Woo Park
Korean Diabetes J. 1999;23(6):785-792.   Published online January 1, 2001
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AbstractAbstract PDF
BACKGROUND
Diabetes mellitus is a known risk factor for atherosclerosis, and lipid peroxidation, expression of oxidative stress, is also known to related to diabetes mellitus. The purpose of this study was to investigate the proliferative behaviour of cultured vascular smooth muscle cells (VSMCs) and the alteration of lipid peroxidation in relation to the pathogenesis of diabetic atherosclerosis. METHODS: Seven streptozotocin-induced insulin dependent diabetic Sprague Dawley rats and 7 normal rats were studied. Using enzyme method, aortic VSMCs was cultured in diabetic rats. and proliferation was compared between normal and diabetic rat. The membrane lipid peroxidaton of erythrocytes was determined by measurement of malonyl- dialdehyde(MDA), an end-product of fatty acid peroxidation with thiobarbituric acid (TBA) reaction. MDA-TBA colored complex concentration was calculated with the extinction coefficient of MDA-TBA complex at 532nm = 1.56X105cm-lM-1. RESULT: 1. The proliferative ability of cultured VSMCs was much higher in diabetic rats than in nondiabetic ones (p<0.05). 2. Compared with normal control rats, MDA concentration of diabetic rats was significantly increased (p<0.05). CONCLUSION: We concluded that proliferation of cultured VSMCs is due to oxidative stress in diabetes mellitus as a result of the increased proliferative ability of cultured VSMCs combined with increased lipid pemxidation in diabetic rats.
Differential Activation of the Renal Renin-Angiotensin System Components in Diabetic Rats.
Woon Jung Kim, Mi Young Lee, Tae Hyung Kim, Eun Kyoung Yang, Won Jung Lee
Korean Diabetes J. 1998;22(2):218-230.   Published online January 1, 2001
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  • 19 Download
AbstractAbstract PDF
BACKGROUND
The renin-angiotensin system(RAS) plays an important role in the physiologic regulation of the renal microcirculation and may contribute to the imbalance of resistances present at the preglomerular and postglomerular sites whirh are responsible for glomerular capillary hypertension, a major injurious factor in the diabetic kidney. Blockade of angiotensin(Ang II) with angiotensin converting enzyme(ACE) inhibitor or Ang II receptor antagonists reduces glomerular injury. However, the relationship between diabetes and the RAS is unclear. METHOD: To investigate changes of gene expression of the renal renin-angiotensin system in diabetic nephropathy, mRNA levels of the RAS components were determined with the methods of Northern blot and RT-PCR in streptozotocin-induced diabetic(STZ-D) rats. Sprague-Dawley rats(240~260 g) were made diabetic by double i.p. injections of 45 mg/kg STZ. Result: Plasma renin concentration increased significantly at the onset of diabetes, and then suppressed at 4 and 8 week sof diabetes. Changes in renal renin content and mRNA levels were in parallel with plasma renin concentration during 8 weeks of diabetes. Renal angiotensinogen mRNA levels of the STZ-D rats decreased initially and then returned to the baseline with the progression of diabetes. Gene expression of angiotensin II-AT1 receptor subtypes, AT1a and AT1b, was not significantly changed during 8 wk of diabetes. Plasma and renal ACE activity increased significantly at 4 and 8 wk of diabetes. CONCLUSION: Results of the present study show a marked decrease in renal renin mRNA levels and renin concentration, but significant increase in ACE activity in chronic diabetic rats. When considering renoprotective effect of ACE inhibitors and AT receptor antagonists, the present result may suggest an increased intrarenal generation of Ang II and its pathophysiologic role in diabetic nephropathy. However, further studies are required to clarify meanings of the differential activation of the renal renin-angiotensin system components in diabetic rats.
Effect of Aminoguanidine on Lipid Peroxidation in Streptozotocin-induced Diabetic Rats.
Kwon Yeop Lee, Sung Hee Ihm, Hyung Joon Yoo, Sung Woo Park, Ja Hei Ihm
Korean Diabetes J. 1997;21(4):372-380.   Published online January 1, 2001
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  • 18 Download
AbstractAbstract PDF
BACKGROUND
Diabetes mellitus is postulated to be associated with increased lipid peroxidation which may contribute to vascular complications. One potential mechanism of the increased lipid peroxidation in diabetes is lipid-linked advanced glycosylation and oxidation. Aminoguanidine(AMGN), the prototype inhibitor of advanced glycosylation end-product formation, has been recently shown to prevent oxidative moditication of LDL in vitro at moderate concentration. It is unknown whether AMGN might act as an anti-oxidant against lipid peroxidation under hyperglycemia in vivo. METHODS: To investigate the in vivo effect of AMGN on lipid peroxidation in diabetes, we administered AMGN(1 g/L in drinking water) or vitamin E (400mg/day, 5 days/week) to streptozotocin(STZ)-induced diabetic rats for 9 weeks and measured plasma lipid hydroperoxides by ferrous oxidation with xylenol orange II method and RBC membrane malon-dialdehyde(MDA) by thiobarbituric acid method. RESULTS: Plasma lipid hydroperoxide level was higher in STZ-induced diabetic rats than in control rats(7.53+/-2.03 vs.5.62+/-0.44*pmol/L). RBC membrane MDA was also higher in STZ-induced diabetic rats than in control rats(2.67+/-0.46 vs. 1.81+/-0.19* nmol/mL). Plasma lipid hydroperoxide level was lower in AMGN-treated(6.23+/-0.59*umol/L) and vitamin E-treated(5.29+/-0.27*umol/L) diabetic rats than in untreated diabetic rats. RBC membrane MDA was also lower in AMGN-treated(1.93+/-0.12""'nmol/ mL) diabetic rats than in untreated diabetic rats. There was no significant difference in plasma glucose, triglyceride levels among diabetic groups(Mean +/-S.D; *, P<0.05 vs. untreated STZ-induced diabetic rats; n=8-14/group). CONCLUSION: Although the mechanisms of action of AMGN on lipid peroxidation in vivo should be studied further, these results suggest that AMGN might have an additional beneficial effect as an antioxidant against lipid peroxidation in prevention trial for diabetic vascular complications.
Lipopolysaccharide-Induced Changes in Vascular Reactivity of Diabetic Rat Aorta.
Ye Kyung Seo, Sang Won Chung, Jik Hwa Nam, Byoung Ho Sin, Dong Hee Kim, Jung Guk Kim, Sung Woo Ha, Bo Wan Kim
Korean Diabetes J. 1997;21(3):280-288.   Published online January 1, 2001
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AbstractAbstract PDF
Backgound: Hemodynamic deteriorations in diabetes mellitus may be mediated by increased contractile response to catecholamines and/or by decreased relaxative response to vasodilators such as acetylcholine(Ach). Decrease in peripheral vascular reactivity to vasoconstrictor was known to be an ominous sign that happens during sepsis or after injection of bacterial lipopolysaccharides(LPS). In this study, we compared the effects of LPS on function of diabetic rat aorta with impaired vascular reactivity with those of control rat aorta. METHODS: Contractile responses to cumulative concentrations(10'M to 3X10'M) of norepinephrine (NE) were measured in aorta isolated ftom the control and 4 to 5-week streptozotocin-induced diabetic rat at 6 hours after LPS treatment to compare with contractile responses of untreated group. We measured relaxative responses to cumulative concentrations(10'M to 10M) of Ach and nitroprusside (NTP) in these aortas contracted submaximally by NE. RESULTS: Diabetic rat aortas showed significantly more impairment in relaxative responses to Ach than control rat aortas before LPS treatment(p0.05 = 0.0l). LPS treatment in those diabetic rat aortas decreased contractile responses to NE by 26.6%(p < 0.01); the changes were sirnilar to those of control (30.9%, p0.01). Relaxative responses to Ach were also significantly decreased by 25.0%(p 0.01) after L.PS treatment; the changes were similar to those of control(34.1%, p0.01). However relaxative responses to NTP were not changed in control and d.iabetic rat aortas by LPS treatment. CONCLUSION: These results suggest that diabetes may induce impairment in endothelium-dependent vascular relaxation and there rnay be no difference of L,P,S-induced effects on hemodynamic deterioration between 4 to 5-week diabetic and control rats.

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