[Show abstract][Hide abstract] ABSTRACT: Background/aims:
Telmisartan and losartan, angiotensin II type 1 (AT1) receptor antagonists, are used to manage hypertension. We previously reported that telmisartan, a partial agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ), exhibited stronger vasoprotection than the same dose of losartan in normotensive chronic kidney disease (CKD) rats. We investigated whether telmisartan could inhibit vascular dysfunction in hypertensive CKD rats, via both AT1 receptor blockade and PPAR-γ activation, more effectively than losartan, which decreased blood pressure to a similar extent as telmisartan.
Two or three branches of the left renal artery were ligated and the right kidney was removed to make hypertensive CKD rats. Telmisartan (5 mg/kg), losartan (10 mg/kg) or telmisartan plus the PPAR-γ antagonist GW9662 was administered.
Blood pressure was increased in CKD rats. Telmisartan and losartan decreased blood pressure to the same levels. Impaired endothelium-dependent vasodilation, hyperplasia and decreased phospho-eNOS (Ser(1177)) expression in CKD rat aortas were improved by telmisartan. The aortic infiltration by macrophages and expression of osteopontin were enhanced in CKD rats and suppressed by telmisartan. GW9662 partly canceled the normalization of vascular dysfunction. While losartan attenuated vascular changes, the extent of this attenuation was greater in the telmisartan-treated group.
Telmisartan exhibited vasoprotection via PPAR-γ agonistic properties in hypertensive CKD rats.
[Show abstract][Hide abstract] ABSTRACT: Erythropoietin (EPO) has been used for the management of renal anemia. Recent studies suggest the pleiotropic properties of EPO in various tissues such as brain, kidney and vasculature. Diabetes mellitus is a major risk for development of vascular impairment. The aim of the present study was to investigate the hypothesis that EPO would be beneficial in inhibiting diabetic macroangiopathy. Recombinant human EPO (rHuEPO; 150 U/kg, 3 times/week, s.c.) was administered to streptozotocin-induced diabetic rats for 4 weeks. Streptozotocin (65 mg/kg, i.v.) significantly increased macrophage infiltration and adhesion molecules, monocyte chemoattractant protein-1 and osteopontin mRNA levels in the aorta. These inflammatory changes were suppressed by rHuEPO. Vasodilation in response to acetylcholine in the aortic ring was impaired in the diabetic rats, and improved by rHuEPO. rHuEPO inhibited the aortic expression of mRNA for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and the NADPH oxidase-dependent superoxide production and the increase in plasma malondialdehyde concentration in diabetic rats. rHuEPO also decreased the level of the receptor for advanced glycation end products in the aorta. We also found an increased expression of phospho-Akt and endothelial nitric oxide synthase and plasma NOx level in the rHuEPO-treated group. On the other hand, rHuEPO did not affect blood glucose levels, hemoglobin A(1c), blood pressure or hematocrit in diabetic rats. These results indicate that rHuEPO exerts pleiotropic antioxidant and anti-inflammatory properties in diabetic rat aorta.
[Show abstract][Hide abstract] ABSTRACT: Objectives: We and other researchers reported that nitric oxide (NO) plays an important role in pleiotropic tissue-protective effects of erythropoietin (ISH 2010, Vancouver). This study was aimed to investigate the other mechanisms of erythropoietin-induced vasoprotection using NO synthase inhibitor-treated rats. Design and methods: Erythropoietin (75 U/kg, s.c.) was administered to NO synthase inhibitor (L-NAME, 0.7 mg/ml in drinking water)-treated rats for 2 weeks. Systolic blood pressure (SBP) and hematocrit was measured, and aorta was excised for the following investigations. Acetylcholine-induced relaxation was determined. Cryosections were prepared to detect macrophages and osteopontin by immunohistochemistry and to stain with hematoxylin-eosin. Immunoblotting was performed to assay the phospho-Akt, heme oxygenase-1 (HO-1), Cu/Zn-superoxide dismutase (SOD) and suppressor of cytokine signaling 1 (SOCS1) proteins. NADPH oxidase was measured by a luminescence assay. In addition, erythropoietin was administered to angiotensinII-treated cultured vascular endothelial cells with/without STAT5 inhibitor. Results: There was no significant difference in hematocrit among all groups. Erythropoietin had no effect on the increased SBP in L-NAME-treated rats. Erythropoietin improved endothelium-dependent vasodilatation. Macrophage infiltration, overexpression of osteopontin, and hyperplasia in L-NAME-treated rats were reduced by erythropoietin. Erythropoietin enhanced the levels of phospho-Akt, HO-1 and Cu/Zn-SOD protein. The increased NADPH oxidase activity in L-NAME-treated rat was suppressed by erythropoietin. Erythropoietin also induced SOCS1 overexpression. Cotreatment with STAT5 inhibitor canceled erythropoietin-induced suppression in NADPH oxidase activation in angiotensinII-treated endothelial cells. 1. Simopoulos AP, Cleland LG, editors. Omega-6/Omega-3 Essential Fatty Acid Ratio: The Scientific Evidence in World Rev Nutr Diet, Basel, Karger, 2003: 92:1-22. 2. Na S, Collin O, Chowddury F, Tay B, Ouyang M, Wang Y, Wang N. Rapid signal transduction in living cells is a unique feature of mechanotransduction. Proc Natl Acad Sci USA 2008; 105: 186626-186631. 3. Hoffman BD, Grashoff C, Schwartz MA. Dynamic molecular processes mediate cellular mechanotransduction. Nature 2011; 475(7356): 316-323.
No preview · Article · Sep 2012 · Journal of Hypertension
[Show abstract][Hide abstract] ABSTRACT: Erythropoietin (EPO), used clinically for renal anemia, reportedly exerts beneficial pleiotropic effects in various tissues. Recent studies suggest that nitric oxide (NO) plays an important role in EPO-induced tissue protection. The present study investigated whether recombinant human EPO (rHuEPO) exhibits vasoprotective effects even in the NO synthase-inhibited state. Rats that received a NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), in drinking water (0.7 mg/ml) were treated with rHuEPO (75 U/kg, s.c.) three times a week for 2 weeks. The administration of rHuEPO to L-NAME-treated rats had no effect on hematocrit values or increased blood pressure. Vasodilation in response to acetylcholine in the aortic ring was impaired in the L-NAME-treated rats, and improved by rHuEPO. Immunohistochemical staining revealed that infiltration by macrophages and expression of osteopontin were enhanced in the L-NAME-treated rat aorta, and the overexpression was suppressed by rHuEPO. rHuEPO also attenuated medial hyperplasia. Activation of Akt signaling was evident in rHuEPO-treated rats as the increased expression of phosphorylated Akt. rHuEPO enhanced the expression of antioxidant enzymes such as Cu/Zn-superoxide dismutase and heme oxygenase-1 in the aorta. In addition, rHuEPO reduced NADPH oxidase-dependent superoxide production and enhanced the expression of suppressor of cytokine signaling-1(SOCS-1) in the L-NAME-treated rat aorta. These results suggest that a low dose of rHuEPO results in the normalization of endothelial function and vascular inflammation beyond hematopoiesis even in a pharmacologically NO synthase-inhibited state. These effects might be due to the antioxidant properties of rHuEPO. SOCS-1 overexpression would play an important role in suppressing NADPH oxidase activation.
No preview · Article · Jul 2012 · European journal of pharmacology
[Show abstract][Hide abstract] ABSTRACT: Reactive oxygen species are exacerbating factors in failing hearts. We examined whether spironolactone, a mineralocorticoid receptor antagonist, provides additional effects to olmesartan, an angiotensin II receptor blocker, on oxidative stress in postinfarct failing hearts. Congestive heart failure due to myocardial infarction (MI) was induced by the coronary artery ligation in rats. Three weeks later, the rats were divided into 4 groups: an untreated MI group, spironolactone (100 mg·kg·d)-treated MI group, olmesartan (10 mg·kg·d)-treated MI group, and combination-treated (spironolactone and olmesartan) MI group. After 7 weeks of MI, monotherapy improved left ventricular dilatation and function, and suppressed myocardial lipid peroxidation, in association with an attenuation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent and mitochondrial superoxide production. Moreover, combination therapy caused a synergistic improvement in these indices. In experiments using cultured myocytes, aldosterone (100 nmole/L) and angiotensin II (100 nmole/L) enhanced both sources of superoxide production, although these humoral factors affected NADPH oxidase subunits (p47phox and gp91phox) differently. In conclusion, aldosterone and angiotensin II increase NADPH oxidase-dependent and mitochondrial superoxide production in myocytes, and the combination of an angiotensin II receptor blocker and mineralocorticoid receptor antagonist has a synergistic attenuation of cardiac oxidative stress, leading to an improvement in cardiac function in postinfarct failing hearts.
No preview · Article · Apr 2012 · Journal of cardiovascular pharmacology
[Show abstract][Hide abstract] ABSTRACT: Telmisartan, an angiotensin II type 1 receptor blocker, reportedly exhibits a partial peroxisome proliferator-activated receptor (PPAR)-γ agonistic action. To test whether telmisartan ameliorates vascular injury in the chronic kidney disease model rat through the PPAR-γ pathway, telmisartan (5 mg/kg per day, orally), losartan (5 mg/kg per day, orally) or telmisartan plus PPAR-γ antagonist, GW9662 (1 mg/kg/day, i.p.), was administered for 14 days to subtotal nephrectomized rats (Nx). There was no significant difference in systolic blood pressure or fasting blood glucose values among all groups. Subtotal nephrectomy significantly aggravated the levels of urinary protein excretion, blood urea nitrogen and plasma malondialdehyde concentration, which were attenuated by telmisartan or losartan treatment. Vasodilation in response to acetylcholine in the aortic ring was impaired in the Nx, and improved by treatment with telmisartan. Immunohistochemical analysis revealed that the infiltration of adventitial areas by macrophages and expression of osteopontin and vascular cell adhesion molecule-1 were enhanced in the Nx aorta and the overexpression was suppressed by telmisartan. The increased NADPH oxidase-derived superoxide production in the aorta from the Nx rat was suppressed by telmisartan. Cotreatment with GW9662 partly blunted the normalization of vascular dysfunction and inflammation. While losartan also attenuated these vascular changes in the Nx rats, the extent of the attenuation was significantly greater in the telmisartan-treated group than in the losartan-treated group. These results suggest that, in addition to a class effect of angiotensin II type 1 receptor blockers, telmisartan exerted vasoprotective effects through its PPAR-γ agonistic property in rats with renal failure.
No preview · Article · Jan 2012 · European journal of pharmacology
[Show abstract][Hide abstract] ABSTRACT: Recombinant human erythropoietin (rHuEPO), used clinically for renal anemia, reportedly exhibits pleiotropic properties in various tissues. To test whether it ameliorates vascular injury, rHuEPO (75U/kg) was administered subcutaneously every 3days for 10days to 5/6 nephrectomized hypertensive rats (5/6Nx) treated with 1% NaCl. rHuEPO had no effect on increased systolic blood pressure or decreased hematocrit values, but normalized levels of proteinuria and creatinine clearance. Vasodilation in response to acetylcholine in the aortic ring was impaired in the 5/6Nx, and improved by treatment with rHuEPO. Immunohistochemical analysis revealed that the infiltration of adventitial areas by macrophages and expression of osteopontin were enhanced in the 5/6Nx aorta and the overexpression was suppressed by rHuEPO. rHuEPO also attenuated medial hyperplasia. Akt signaling was activated by the increased expression of phosphorylated Akt and GSK-3β in aorta from rHuEPO-treated 5/6Nx. rHuEPO restored plasma NOx (NO(2)(-)+NO(3)(-)) levels and endothelial nitric oxide synthase (eNOS) content in the 5/6Nx aorta. Treatment with an eNOS substrate, l-arginine, which caused a similar increase in plasma NOx levels as the rHuEPO treatment, resulted in a normalization of endothelial dysfunction and vascular inflammation. These results suggest that a low dose of rHuEPO exerted vasoprotective effects in rats with hypertensive renal failure.
No preview · Article · Feb 2011 · European journal of pharmacology
[Show abstract][Hide abstract] ABSTRACT: Cilnidipine, an N/L-type calcium channel blocker, has been reported to inhibit sympathetic nerve activity and has a greater renoprotective effect than L-type calcium channel blockers. To investigate the hypothesis that cilnidipine might ameliorate advanced hypertensive nephropathy and inhibit the renal renin-angiotensin-aldosterone system, cilnidipine (1 mg per kg per day) or amlodipine (1 mg per kg per day) was administered to uninephrectomized deoxycorticosterone (DOCA)-salt hypertensive rats (DOCA-salt) for 4 weeks by gavage. Although the blood pressure in the DOCA-salt group was higher than that of control, neither cilnidipine nor amlodipine had any effect on the increase in blood pressure in the DOCA-salt group. The DOCA (40 mg per kg per week, subcutaneously (s.c.)) and salt (1% NaCl in drinking water) treatment significantly aggravated the levels of urinary protein excretion and creatinine clearance and increased glomerulosclerosis and collagen deposition in the tubulointerstitial area of the kidney. These effects were attenuated by cilnidipine treatment. Reverse transcription-polymerase chain reaction analysis revealed that the renal expression of mRNA for collagen I/IV and transforming growth factor-β was enhanced in the DOCA-salt group and that the overexpression of these molecules was suppressed by cilnidipine. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived superoxide production in the kidney and urinary norepinephrine excretion, which were enhanced in the DOCA-salt group, were suppressed by cilnidipine. Cilnidipine also decreased the activity and expression of angiotensin-converting enzyme (ACE) and the aldosterone concentration in the renal homogenate. Although neither cilnidipine nor amlodipine had any effect on the increased blood pressure in the DOCA-salt group, these renal changes were not induced by treatment with amlodipine. In conclusion, cilnidipine inhibited renal dysfunction, sympathetic nerve activity and renal renin-angiotensin-aldosterone system in the DOCA-salt group.
No preview · Article · Jan 2011 · Hypertension Research
[Show abstract][Hide abstract] ABSTRACT: 1. Recombinant human erythropoietin (rHuEPO) has been used for the management of renal anaemia. Recent studies suggest pleiotropic properties of rHuEPO in various tissues. The aim of the present study was to investigate the vasoprotective effects of rHuEPO in renal failure rats.
2. Rats subjected to 5/6 and 17/18 nephrectomy (5/6Nx and 17/18Nx rats, respectively) were treated with rHuEPO (75 U/kg, s.c.) three times a week for 2 weeks.
3. Administration of rHuEPO to 5/6Nx or 17/18Nx rats had no effect on systolic blood pressure or decreased haematocrit. However, rHuEPO treatment normalized proteinuria and creatinine clearance in 5/6Nx, but not in 17/18Nx, rats.
4. Vasodilation in response to acetylcholine in aortic rings was impaired in 5/6Nx and 17/18Nx rats and improved by rHuEPO in both groups. Immunohistochemical analysis revealed that macrophage infiltration into adventitial areas and the expression of osteopontin were enhanced in aortas from 5/6Nx and 17/18Nx rats, but that rHuEPO suppressed these effects. In addition, rHuEPO attenuated medial hyperplasia and NADPH oxidase-derived superoxide production in 5/6Nx and 17/18Nx rats.
5. Activation of the Akt signalling pathway was evident in rHuEPO-treated rats as the increased expression of phosphorylated Akt and glycogen synthase kinase-3β. Treatment with rHuEPO restored the expression of phosphorylated endothelial nitric oxide synthase in the aorta and urinary excretion of NOx in nephrectomized rats.
6. These results suggest that a low dose of rHuEPO results in the normalization of endothelial function, vascular inflammation and oxidative stress in rats with renal ablation beyond haematopoiesis. In addition, these vasoprotective effects are observed even in a state of deteriorating renal dysfunction.
No preview · Article · Dec 2010 · Clinical and Experimental Pharmacology and Physiology
[Show abstract][Hide abstract] ABSTRACT: 1. The aim of the present study was to investigate whether or not pitavastatin ameliorates diabetic nephropathy and if inhibition of the rennin–angiotensin–aldosterone system (RAAS) is associated with any renoprotective effects. Pitavastatin (10 mg/ kg/day) and/or spironolactone (100 mg/kg/day) were given by gavage for 3 weeks to uninephrectomized rats with streptozotocin-induced diabetes.
2. Pitavastatin or spironolactone significantly reduced proteinuria and collagen deposition, and normalized creatinine clearance, serum creatinine levels and blood urea nitrogen concentrations.
3. Reverse transcription polymerase chain reaction analysis showed that the renal expression of collagen I, transforming growth factor-β and monocyte chemoattractant-1 were increased in diabetic rats and reduced by the pitavastatin and/or spironolactone treatment.
4. These agents also decreased angiotensin converting enzyme expression and aldosterone concentrations in the renal homogenate, but had no effect on blood glucose, haemoglobinA1c, and plasma total cholesterol, Na+, K+, aldosterone and NOx levels, or on systolic blood pressure measured by the tail-cuff method. Interestingly, cotreatment with pitavastatin and spironolactone did not result in additional normalization.
5. These results suggest that pitavastatin shows renoprotective effects against diabetic nephropathy mediated in part by inhibition of the renal RAAS, including the suppression of angiotensin-converting enzyme expression and aldosterone production.
No preview · Article · Nov 2010 · Clinical and Experimental Pharmacology and Physiology