Beneficial Effects of Combination Therapy with Olmesartan and Azelnidipine in Murine Polycystic Kidneys

Tanifuji, Chiaki; Suzuki, Yusuke; Geot, Wong Mu; Horikoshi, Satoshi; Takahashi, Hisahide; Tomino, Yasuhiko

doi:10.1159/000238821

Cited by 10 publications

(8 citation statements)

References 59 publications

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“…In a murine model of polycystic kidney disease, combination therapy with olemsartan and azelnidipine retarded cyst growth by reducing interstitial inflammation and oxidative stress (26). A crossover study of simvastatin in 10 normocholesterolaemic patients with ADPKD showed improvements in renal blood flow and endothelial function, actions that may involve known pleiotropic effects of statins including anti-inflammatory effects (27).…”

Section: Discussionmentioning

confidence: 99%

Inflammation, Oxidative Stress, and Insulin Resistance in Polycystic Kidney Disease

Menon

Rudym

Chandra

et al. 2011

Clinical Journal of the American Society of Nephrology

127

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SummaryBackground and objectives Most deaths in autosomal dominant polycystic kidney disease (ADPKD) are attributable to cardiovascular disease (CVD). We examined novel CVD biomarkers in different stages of AD-PKD.Design, setting, participants, & measurements We recruited 50 hypertensive subjects with ADPKD with estimated GFR (eGFR) of Ͼ60 ml/min per 1.73 m 2 ; 52 hypertensive subjects with ADPKD with eGFR of 25 to 60 ml/min per 1.73 m 2 ; 42 normotensive subjects with ADPKD and eGFR of Ͼ60 ml/min per 1.73 m 2 ; and 50 healthy controls. We assayed serum C-reactive protein and IL-6 as markers of inflammation; plasma 8-epi-prostaglandin F 2␣ (8-epi-PGF2␣ ) and superoxide dismutase (SOD) as markers of oxidative stress; and homeostasis model assessment (HOMA) as a measure of insulin resistance. ResultsThe hypertensive ADPKD eGFR of 25 to 60 group had higher levels of C-reactive protein and IL-6 than controls, normotensive ADPKD with eGFR of Ͼ60, and hypertensive ADPKD with eGFR of Ͼ60. The normotensive ADPKD eGFR Ͼ60, hypertensive ADPKD eGFR Ͼ60, and hypertensive ADPKD eGFR 25 to 60 groups had higher 8-epi-PGF 2␣ and lower SOD than controls, with no difference between the ADPKD groups. There was no difference in HOMA levels between any of the groups. Adjustment for age, race, gender, and body mass index did not alter these relationships. ConclusionsInflammation and oxidative stress are evident early in ADPKD even with preserved kidney function. Inflammation exhibits a graded relationship with levels of kidney function, whereas oxidative stress demonstrates a threshold effect. These pathways may be therapeutic targets for CVD risk mitigation.

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Section: Discussionmentioning

confidence: 99%

Inflammation, Oxidative Stress, and Insulin Resistance in Polycystic Kidney Disease

Menon

Rudym

Chandra

et al. 2011

Clinical Journal of the American Society of Nephrology

127

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“…This suggests that the treatment may affect macrophage infiltration to the glomerulus, fibroblast accumulation in the glomerulus, mesangial activation, and podocyte differentiation [20]. Combination therapy protects against cyst enlargement in polycystic kidney disease by suppressing interstitial inflammation, fibrosis, and oxidative stress through upregulating eNOS expression during the course of the disease [21]. Taken together, the combination of OLM plus AZL provides additional cardiovascular protective effects on arterial stiffness resulting in an improvement in the CAVI.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects in Cardiovascular Markers between High-Dose Angiotensin II Receptor Blocker Monotherapy and Combination Therapy of ARB with Calcium Channel Blocker in Hypertension (DEAR Trial)

Kinouchi

Ichihara

Bokuda

et al. 2011

International Journal of Hypertension

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Background/Aims. Arterial stiffness is an independent risk factor for cardiovascular morbidity and mortality. This study was conducted to determine the effect of olmesartan (OLM) and azelnidipine (AZL) on arterial stiffness using the cardio-ankle vascular index (CAVI), which is a novel blood pressure (BP)-independent marker for arterial stiffness in hypertensive patients. Methods. Fifty-two consecutive hypertensive patients were randomly assigned either to a group treated with OLM monotherapy or to a group treated with OLM and AZL combination therapy. Clinical and biological parameters were measured before and 12 months after the start of this study. Results. Both therapies significantly and similarly reduced BP, augmentation index, and plasma aldosterone levels. The combination therapy significantly decreased CAVI and serum low-density lipoprotein (LDL-C) levels and these reductions were significantly greater than those produced with monotherapy. No significant differences in metabolic parameters were observed between the two therapies. Conclusion. The combination therapy with OLM and AZL had beneficial effects on arterial stiffness assessed by CAVI, LDL-C, and metabolism, despite the similar BP reduction, compared with OLM monotherapy. Since these markers are known to influence the future risk of cardiovascular events, combination therapy with OLM and AZL could be a useful choice for treating hypertensive patients.

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“…One explanation for this result could be the antioxidant action of OLM and AZN, which occurs by inducing superoxide dismutase activity in blood vessels 31) or by suppressing ROS production. [32][33][34][35][36][37][38][39][40][41] OLM is known to block angiotensin II induced superoxide production by reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. 42) In addition, AZN has reported to attenuate ROS production via suppression of NADPH oxidase in a manner similar to OLM, 19,32) and is a more potent antioxidant than any other dihydropyridine calcium antagonists because of its good liposolubility and vascular endothelial penetration.…”

Section: Discussionmentioning

confidence: 99%

“…9) Similar to these results, we found increased MCP-1 expression in the vehicle group and decreased expression in the OLM and AZN groups. Based on these findings, we considered that the antioxidant effects of OLM and AZN suppressed not only AIM expression but also MCP-1 expression; further, these drugs reduced the number of infiltrating macrophages, resulting in the inhibition of interstitial fibrosis [32][33][34][35][36][37][38][39][40][41] . Currently, it is not yet clarified which drug, OLM or AZN, is stronger on antioxidant effects, future studies comparing OLM and AZN are required to determine which of these is a stronger antioxidant.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Apoptosis Inhibitor of Macrophages in a Rat Hypertension Model with Nephrosclerosis: Possible Mechanisms of Action of Olmesartan and Azelnidipine

Uramatsu

Nishino

Obata

et al. 2013

Biological & Pharmaceutical Bulletin

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Stroke-prone spontaneously hypertensive (SHRsp) rats develop severe hypertension resulting in renal injury. We investigated apoptosis inhibitor of macrophages (AIM) expression in nephrosclerotic rats and the involvement of AIM in olmesartan (OLM)-and azelnidipine (AZN)-induced decreases in the number of macrophages infiltrating the kidney. We randomly assigned 20-week-old male SHRsp rats to receive one of the following substances every day for 12 weeks: water (vehicle), hydralazine (HYD), OLM, or AZN. Renal damage was assessed by Masson trichrome staining. Expressions of ED-1, AIM, and oxidized low-density lipoprotein (oxLDL) were immunohistochemically detected. Apoptosis was analyzed by terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) staining. All treatment groups showed significantly less renal interstitial fibrosis than the vehicle group. AZN and OLM groups had significantly fewer AIM-expressing cells than the HYD and vehicle groups. The ratios AIM-positive cells/ ED-1-positive macrophages and TUNEL-positive cells/ED-1-positive macrophages in the AZN and OLM groups were lower and higher, respectively, than the the HYD and vehicle groups. oxLDL expression in the renal interstitium was significantly lower in treatment groups compared to vehicle group. OLM and AZN inhibited interstitial fibrosis progression in SHRsp rats by suppressing AIM expression in macrophages, followed by reducing the number of infiltrating macrophages. Key words apoptosis; macrophage; nephrosclerosis; oxidized low-density lipoproteinThe number of patients with chronic kidney disease (CKD) has increased dramatically worldwide.1) A follow-up of the National Health and Nutrition Examination Surveys in the United States reported that the frequency of CKD (stages 1-4) increased from 10.0% in 1988-1994 to 13.1% in 1999-2004. 2) CKD is an independent risk factor (heart-and kidney-related) of cardiovascular disease, and is known to increase the risks for angina pectoris, myocardial infarction, cardiac arrest, cerebrovascular disorders, peripheral vascular disease, death due to cardiovascular disease, and sudden death. 3,4) Nephrosclerosis is one of the main diseases underlying CKD.5) It involves progressive arteriosclerosis at the level of the small arteries and arterioles in the kidneys, leading to ischemic changes in the glomeruli and interstitium, consequently compromising renal function.6) This increased arteriosclerosis due to long-term hypertension associated with aging has resulted in the increased global incidence of nephrosclerosis.Previous studies have reported that macrophages play a major role in the progression of arteriosclerosis in humans and in animal models. Further, macrophage infiltration is closely associated with the onset and progression of myocardial infarction, cerebrovascular disorders, and arteriosclerotic diseases such as nephrosclerosis. [7][8][9][10][11][12] Apoptosis inhibitor of macrophages (AIM) is a secretory protein comprising 3 scavenger receptor cystein-rich...

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Beneficial Effects of Combination Therapy with Olmesartan and Azelnidipine in Murine Polycystic Kidneys

Cited by 10 publications

References 59 publications

Inflammation, Oxidative Stress, and Insulin Resistance in Polycystic Kidney Disease

Inflammation, Oxidative Stress, and Insulin Resistance in Polycystic Kidney Disease

Differential Effects in Cardiovascular Markers between High-Dose Angiotensin II Receptor Blocker Monotherapy and Combination Therapy of ARB with Calcium Channel Blocker in Hypertension (DEAR Trial)

Involvement of Apoptosis Inhibitor of Macrophages in a Rat Hypertension Model with Nephrosclerosis: Possible Mechanisms of Action of Olmesartan and Azelnidipine

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