Chronic Angiotensin II Receptor Blockade Reduces (Intra)Renal Vascular Resistance in Patients with Type 2 Diabetes

Fliser, Danilo; Wagner, Kathrin-Kristin; Loos, Astrid; Tsikas, Dimitrios; Haller, Hermann

doi:10.1681/asn.2004100852

Cited by 90 publications

(55 citation statements)

References 39 publications

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“…Moreover, modulation of DDAH activity to lower plasma ADMA levels may represent a novel therapeutic target to retard progression. In this respect, inhibition of the renin-angiotensin system may not be enough, because we could not find a significant effect of chronic angiotensin II receptor blockade on plasma ADMA concentrations in a recent double-blind, placebo-controlled, randomized study (33). Thus, other treatment strategies to reduce ADMA in patients with kidney diseases should be evaluated.…”

Section: Discussionmentioning

confidence: 88%

Asymmetric Dimethylarginine and Progression of Chronic Kidney Disease

Fliser

Kronenberg

Kielstein

et al. 2005

Journal of the American Society of Nephrology

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Reduced bioavailability of nitric oxide (NO) is thought to play an important role in progression of renal damage. The hypothesis that the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is involved in progression of kidney disease was tested. Plasma ADMA concentrations and other putative progression factors were assessed in 227 relatively young patients (45.7 ؎ 12.6 yr) with nondiabetic kidney diseases and mild to moderate renal failure. Progression assessed as doubling of serum creatinine and/or renal replacement therapy was evaluated prospectively. Baseline plasma ADMA concentrations in renal patients correlated significantly with serum creatinine (r ‫؍‬ 0.595), GFR (r ‫؍‬ ؊0.591), age (r ‫؍‬ 0.281), and proteinuria (r ‫؍‬ 0.184; all P < 0.01). Patients who reached an end point during follow-up were significantly older (P < 0.05) and had significantly higher creatinine, ADMA, and parathyroid hormone blood concentrations and protein excretion rates at baseline, whereas GFR and hemoglobin were significantly lower (all P < 0.01). Cox regression analysis revealed baseline serum creatinine (odds ratio 2.00; 95% confidence interval [CI] 1.61 to 2.49; P < 0.001) and ADMA (odds ratio 1.47; 95% CI 1.12 to 1.93 for an increment of 0.1 mol/L; P < 0.006) as independent predictors of disease progression. In patients with ADMA levels above median, progression was significantly faster (P < 0.0001), and their mean follow-up time to a progression end point was 52.8 mo (95% CI 46.9 to 58.8) as compared with 71.6 mo (95% CI 66.2 to 76.9) in patients with ADMA levels below the median. The endogenous NO synthase inhibitor ADMA is significantly associated with progression of nondiabetic kidney diseases. Lowering plasma ADMA concentrations may be a novel therapeutic target to prevent progressive renal impairment.

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Section: Discussionmentioning

confidence: 88%

Asymmetric Dimethylarginine and Progression of Chronic Kidney Disease

Fliser

Kronenberg

Kielstein

et al. 2005

Journal of the American Society of Nephrology

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301

214

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“…[37][38][39] ARBs, particularly telmisartan and olmesartan, also exert antidiabetic effects through their regulation of insulin sensitivity and reduce not only urinary albumin excretion but also urinary 8-OHdG and L-FABP excretion. 40 Statins have been shown to ameliorate tubular and podocyte injury, preserve GFR and reduce proteinuria in renal disease.…”

Section: Discussionmentioning

confidence: 99%

Additive antioxidative effects of azelnidipine on angiotensin receptor blocker olmesartan treatment for type 2 diabetic patients with albuminuria

et al. 2011

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The present study aimed to determine whether either of two calcium channel blockers affected urinary albumin excretion or urinary levels of 8-hydroxy-2¢-deoxyguanosine (8-OHdG) and liver-type fatty acid-binding protein (L-FABP) in hypertensive diabetic patients with chronic kidney disease (CKD) who were already being treated with maximum doses of the angiotensin II receptor blocker olmesartan. We conducted an open-label, randomized, parallel-controlled study on type 2 diabetic patients with stable glycemic control who were receiving fixed doses of antidiabetic agents. The patients received either 8 mg per day azelnidipine, which was increased up to 16 mg per day (azelnidipine group; n¼34), or 2.5 mg per day amlodipine, which was increased up to 5 mg per day (amlodipine group; n¼33), over a 24-week period. Mean systolic and diastolic blood pressure decreased significantly in both groups, but there was no significant difference between the two groups at the end of the study. Serum creatinine levels and estimated glomerular filtration rate did not differ significantly between the two groups, whereas the urinary albumin/creatinine ratio and 8-OHdG and L-FABP levels decreased significantly in the azelnidipine group compared with the amlodipine group. Plasma aldosterone level was significantly decreased in the azelnidipine group, and its changes correlated significantly with those of urinary 8-OHdG and L-FABP. Our results suggest that the addition of azelnidipine to the maximal recommended dose of olmesartan was more effective in reducing albuminuria and oxidant stress in hypertensive diabetic patients with CKD than the addition of amlodipine. Hypertension Research (2011) 34, 935-941; doi:10.1038/hr.2011.67; published online 9 June 2011 Keywords: aldosterone; calcium channel blocker; chronic kidney disease; diabetic nephropathy; oxidant stress INTRODUCTIONThe importance of strict blood pressure (BP) control in patients with chronic kidney disease (CKD) was emphasized by the Japanese Society of Hypertension recommendations of a target BP of o130/ 80 mm Hg for hypertensive patients with CKD. This target is further reduced to o125/75 mm Hg for diabetic nephropathy patients whose urinary protein excretion is 41 g per day. 1 Reduction in proteinuria using suitable therapeutic interventions, similar to renin-angiotensin system (RAS) blockade an antihypertensive treatment regimen, is associated with a slower decline in renal function compared with other treatment groups with similar BPs. 2,3 RAS blockade with angiotensin-converting enzyme inhibitors or angiotensin II type-1 receptor blockers (ARBs) is currently considered the most effective pharmacological approach for renoprotection. These agents reduce proteinuria more effectively than other antihypertensive drugs, and therefore, RAS inhibitors should be titrated to maximal recommended doses. 1,4 However, it is difficult to control BP with mono-

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“…Pharmacological agents that have been tested for their ability to modify ADMA levels in humans include drugs that interfere with the renin-angiotensin system (RAS) by either blocking the formation [angiotensin-converting enzyme (ACE) inhibitors] or pharmacological action [angiotensin receptor blockers (ARBs)] of angiotensin II (ANG II). Although some investigators found significant reductions of ADMA levels in patients treated with RAS-blocking agents (2,4,9,15,16,27,42), other studies have failed to confirm these findings (10,40). Sound interpretation of the aforementioned clinical trials is complicated due to differences in study design, study cohorts, treatment regimen, and the use of different bioanalytical methods to determine ADMA levels.…”

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confidence: 99%

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Jacobi¹,

Maas²,

Cordasic³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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RH, Hilgers KF. Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice. Am J Physiol Heart Circ Physiol 294: H1058-H1066, 2008. First published December 21, 2007 doi:10.1152/ajpheart.01103.2007.-The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) in angiotensin II (ANG II)-induced hypertension and target organ damage in mice. Mice transgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n ϭ 28) were treated with 1.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II, 3.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II, or phosphate-buffered saline over 4 wk via osmotic minipumps. Blood pressure, as measured by tail cuff, was elevated to the same degree in TG and WT mice. Plasma levels of ADMA were lower in TG than WT mice and were not affected after 4 wk by either dose of ANG II in both TG and WT animals. Oxidative stress within the wall of the aorta, measured by fluorescence microscopy using the dye dihydroethidium, was significantly reduced in TG mice. ANG II-induced glomerulosclerosis was similar between WT and TG mice, whereas renal interstitial fibrosis was significantly reduced in TG compared with WT animals. Renal mRNA expression of protein arginine methyltransferase (PRMT)1 and DDAH2 increased during the infusion of ANG II, whereas PRMT3 and endogenous mouse DDAH1 expression remained unaltered. Chronic infusion of ANG II in mice has no effect on the plasma levels of ADMA after 4 wk. However, an overexpression of DDAH1 alleviates ANG II-induced renal interstitial fibrosis and vascular oxidative stress, suggesting a blood pressure-independent effect of ADMA on ANG II-induced target organ damage. dimethylarginine dimethylaminohydrolase; hypertension; transgenic ASYMMETRIC DIMETHYLARGININE (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is increasingly recognized as a potential risk factor and prognostic biomarker in cardiovascular disease (38). Thus far, elevated ADMA levels have been associated with all established cardiovascular risk factors (38). Furthermore, recent data from genetic mouse models indicate a causal role for ADMA in the pathophysiology of vascular disease (7,19). ADMA derives from the posttranslational methylation of L-arginine residues within proteins catalyzed by enzymes called protein arginine methyltransferases (PRMTs). Upon proteolysis, methylarginines are released into the circulation. Although ϳ15% of ADMA are excreted via the urine, the major elimination occurs through enzymatic degradation (ϳ85%) (1). The enzyme dimethylarginine dimethylaminohydrolase (DDAH), of which two isoforms with distinct tissue distribution have been described, catalyzes the hydrolysis of ADMA to L-citrulline and dimethylamine (38).Thus far, clinical studies have mostly addressed the prognostic value of ADMA in cardiovascular or kidney disease as well as the impact of pharmacological interventions aimed at lowering ADMA levels ...

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Chronic Angiotensin II Receptor Blockade Reduces (Intra)Renal Vascular Resistance in Patients with Type 2 Diabetes

Cited by 90 publications

References 39 publications

Asymmetric Dimethylarginine and Progression of Chronic Kidney Disease

Asymmetric Dimethylarginine and Progression of Chronic Kidney Disease

Additive antioxidative effects of azelnidipine on angiotensin receptor blocker olmesartan treatment for type 2 diabetic patients with albuminuria

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

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