Effect of Spironolactone Therapy on Albuminuria in Patients with Type 2 Diabetes Treated with Angiotensin-Converting Enzyme Inhibitors

ObjectiveTo investigate whether the addition of spironolactone to angiotensin-converting enzyme (ACE) inhibitors further decreases albuminuria in patients with type 2 diabetes mellitus (DM).MethodsWe conducted a prospective open-label trial in patients recruited at the Cleveland Clinic between February 2004 and November 2006. Patients with type 2 DM were eligible if they were older than 18 years of age, had been treated with any ACE inhibitor for longer than 1 month, and had a random urinary albumin to creatinine ratio (ACR) greater than 100 mg/g within 1 month of study entry. Based on screening ACR, patients were assigned to a microalbuminuria group (ACR 100-300 mg/g) or a macroalbuminuria group (ACR > 300 mg/g). Patients were followed up for 12 weeks, with 4 clinic visits, 4 weeks apart. At visit 2, spironolactone, 25 mg once daily, was initiated and continued for 4 weeks. At visit 3, spironolactone was discontinued. Clinical information was obtained at each visit as were serum chemistries and 24-hour urinary albumin excretion.ResultsTwenty-four patients with type 2 DM and albuminuria completed the study. Eleven patients had microalbuminuria and 13 had macroalbuminuria. Following treatment with spironolactone, urinary albumin excretion dropped from a mean ± SD of 404.6 ± 60.9 mg/d to 302.7 ± 52.7 mg/d (25.7% decrease, P < .001). In the microalbuminuria and macroalbuminuria groups, the urinary albumin excretion dropped 27.2% (P = .05) and 24.3% (P = .02), respectively. Despite a significant decrease in systolic blood pressure between visits 2 and 3 (141.2 ± 3.5 to 132.5 ± 3.6 mm Hg; P = .002), this change did not correlate to the change in albuminuria (r² = 0.02; P = .23). There were no withdrawals due to hyperkalemia.ConclusionSpironolactone is effective in further decreasing albuminuria in patients with type 2 DM who are already treated with ACE inhibitors. (Endocr Pract. 2008;14:985-992)     

血管紧张素转换酶基因多态性与2型糖尿病发病的相关性研究

目的:探讨血管紧张素转换酶基因(ACE)多态性与其血清水平及2型糖尿病(T2D)发生的相关性.方法:应用聚合酶链反应检测T2D患者287例和正常对照组307例健康人的ACE基因Alu重复序列的插入/缺失(I/D)多态性,采用全自动生化分析仪检测ACE活性及血脂水平,采用SPSS11.0软件包统计分析基因型分布和等位基因频率与其活性、血脂水平及T2D的相关性.结果:ACE I/D多态性在T2D组(DD:13.36%、ID:45.93%、Ⅱ:40.72%)与对照组(DD:13.24%、ID:43.90%、Ⅱ:42.86%)的基因频率无显著性差异(P0.05).T2D组ACE各基因型之间ACE活性有显著性差异(P<0.01).T2D各基因型的血脂水平分析显示Ⅱ型与DD型之间HDL有显著性差异(P<0.05).结论:ACE基因DD型和D等位基因与ACE活性显著相关,但ACE I/D多态性不是T2DM发生的危险因素且无关,DD型与高HDL水平相关.     

2型糖尿病患者心脏代谢指数与白蛋白尿的关系研究

摘要 目的：探讨2型糖尿病（T2DM）患者心脏代谢指数（CMI）与白蛋白尿的关系。方法：选取2012年2月~2020年7月期间在江苏大学附属医院内分泌代谢科就诊且被诊断为T2DM的患者555例,收集患者的临床资料。根据CMI不同数值将患者分为低CMI（L-CMI）组（n=185）、中CMI（M-CMI）组（n=185）和高CMI（H-CMI）组（n=185）,按照尿白蛋白/肌酐比值（UACR）将研究对象分为正常白蛋白尿组（n=294）、微量白蛋白尿组（n=209）和大量白蛋白尿组（n=52）,然后对CMI与T2DM患者发生异常白蛋白尿的关系进行分析,通过受试者工作特征（ROC）曲线评估CMI对T2DM患者发生异常白蛋白尿的预测价值。结果：不同UACR组的收缩压（SBP）、舒张压（DBP）、体质量指数（BMI）、CMI、甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、糖化血红蛋白（HbA1c）、空腹血糖（FPG）、空腹胰岛素（FINS）、空腹C肽（FC-P）、稳态模型评估胰岛素抵抗指数（HOMA-IR）、尿素氮（BUN）、血尿酸（SUA）、血肌酐（Scr）及肾小球滤过率（eGFR）比较均有统计学差异（P＜0.05）。L-CMI组、M-CMI组、H-CMI组异常白蛋白尿发生比例分别为21.08%、42.70%、77.30%,异常白蛋白尿发生比例呈显著递增趋势（P＜0.05）。Spearman秩相关分析结果显示,T2DM患者UACR与FINS、BUN、 CMI、Scr、SUA、SBP、DBP、BMI、TG、TC、HbA1c、FPG、FC-P、HOMA-IR呈正相关（P<0.05）,与eGFR、HDL-C呈负相关（P<0.05）。多元线性回归分析显示,CMI对UACR的影响强度最大（P＜0.05）。Logistic回归分析结果显示,年龄、SBP、CMI、TC、LDL-C及HbA1c是T2DM患者发生异常白蛋白尿的独立危险因素（P＜0.05）。CMI预测异常白蛋白尿发生的曲线下面积为0.801,预测异常白蛋白尿的敏感性、特异性分别为68.60%、76.90%。结论：T2DM患者异常白蛋白尿发生风险与CMI密切相关,提示CMI有望成为临床上糖尿病肾病（DKD）的预测指标。     

Urinary miR-29 Correlates with Albuminuria and Carotid Intima-Media Thickness in Type 2 Diabetes Patients

Background

Cell-free microRNAs stably and abundantly exist in body fluids and emerging evidence suggests cell-free microRNAs as novel and non-invasive disease biomarker. Deregulation of miR-29 is involved in the pathogenesis of diabetic nephropathy and insulin resistance thus may be implicated in diabetic vascular complication. Therefore, we investigated the possibility of urinary miR-29 as biomarker for diabetic nephropathy and atherosclerosis in patients with type 2 diabetes.

Methods

83 patients with type 2 diabetes were enrolled in this study, miR-29a, miR-29b and miR-29c levels in urine supernatant was determined by TaqMan qRT-PCR, and a synthetic cel-miR-39 was added to the urine as a spike-in control before miRNAs extraction. Urinary albumin excretion rate and urine albumin/creatinine ratio, funduscopy and carotid ultrasound were used for evaluation of diabetic vascular complication. The laboratory parameters indicating blood glucose level, renal function and serum lipids were also collected.

Results

Patients with albuminuria (n = 42, age 60.62±12.00yrs) showed significantly higher comorbidity of diabetic retinopathy (p = 0.015) and higher levels of urinary miR-29a (p = 0.035) compared with those with normoalbuminuria (n = 41, age 58.54±14.40yrs). There was no significant difference in urinary miR-29b (p = 0.148) or miR-29c level (p = 0.321) between groups. Urinary albumin excretion rate significantly correlated with urinary miR-29a level (r = 0.286, p = 0.016), while urinary miR-29b significantly correlated with carotid intima-media thickness (cIMT) (r = 0.286, p = 0.046).

Conclusion

Urinary miR-29a correlated with albuminuria while urinary miR-29b correlated with carotid intima-media thickness (cIMT) in patients with type 2 diabetes. Therefore, they may have the potential to serve as alternative biomarker for diabetic nephropathy and atherosclerosis in type 2 diabetes.     

作为肾素-血管紧张素系统调节器和SARS病毒受体的人血管紧张素转换酶2

人血管紧张素转换酶2(ACE2)是目前已知的惟一的人血管紧张素转换酶(ACE)的同源物,是一种新型的金属羧肽酶,很多特性与ACE截然不同.ACE2在肾素-血管紧张素系统(RAS)中具有独特的作用,调节心脏功能和机体血压.最近ACE2被鉴定为SARS病毒的功能受体.ACE2已经成为目前药物研发的新靶点.对ACE2的认识才刚刚开始,有待进-步深入研究.     

Interleukin-2 Receptor and Angiotensin-Converting Enzyme as Markers for Ocular Sarcoidosis

Purpose

To study the impact of soluble IL2 receptor (sIL2R), chest x-ray (CxR), and angiotensin-converting enzyme (ACE) as markers for sarcoidosis in uveitis patients.

Design

Retrospective study.

Methods

Serum concentrations of sIL2R and ACE were measured in patients with active uveitis. Those with elevated sIL2R and /or ACE values were examined for suspected systemic sarcoidosis.

Main Outcome Measure

Our main outcome parameters were the specificity and sensitivity of sIL2R, CxR and ACE in screening for ocular sarcoidosis.

Results

We measured 261 patients with uveitis for sarcoidosis using sIL2R and ACE between January 2008 and November 2011; sarcoidosis was been diagnosed using other tests (e.g. computer tomography, brochoalveolar lavage, biopsy) in 41 of 53 patients with elevated sIL2R values (>639 U/ml) and in one patient with normal sIL2R (582 U/ml). Their mean sIL2R value was 1310 U/ml, extending from 582 to 8659 U/ml. Only 9 patients, however, presented elevated ACE (>82 U/l). Their mean ACE value was 116.4 U/l, ranging from 84.1 to 175.5 U/l. IL2R specificity was 94% with 98% sensitivity. In contrast, ACE had a specificity of 99.5%, but a sensitivity of only 22%; the chest x-ray had a specificity of 100% with 50% sensitivity in detecting sarcoidosis. We observed the entire spectrum of uveitis: sixteen patients suffered from anterior, 8 from intermediate, 16 from posterior, and 2 from panuveitis.

Conclusions

An elevated level of soluble IL2R suggests sarcoidosis with uveitis more convincingly than ACE, making sIL2R a more effective marker parameter for sarcoidosis than ACE or chest x-ray in uveitis patients.     

Meta-Analysis of Combined Therapy with Angiotensin Receptor Antagonists versus ACE Inhibitors Alone in Patients with Heart Failure

Background

There is insufficient evidence whether the benefit of adding angiotensin II receptor blockers (ARBs) to angiotensin-converting enzyme (ACE) inhibitors outweighs the increased risk of adverse effects in patients with heart failure.

Methodology/Principal Findings

Two independent reviewers searched and abstracted randomized controlled trials of ARBs and ACE inhibitors compared to ACE inhibitor therapy alone in patients with heart failure reporting mortality and hospitalizations having a follow-up of at least 6 months identified by a systematic literature search. Eight trials including a total of 18,061 patients fulfilled our inclusion criteria. There was no difference between patients treated with combination therapy and ACE inhibitor therapy alone for overall mortality, hospitalization for any reason, fatal or nonfatal MI. Combination therapy was, however, associated with fewer hospital admissions for heart failure (RR 0.81, 95%CI 0.72–0.91), although there was significant heterogeneity across trials (p-value for heterogeneity = 0.04; I² = 57% [95%CI 0–83%]). Patients treated with combination therapy had a higher risk of worsening renal function and symptomatic hypotension, and their trial medications were more often permanently discontinued. Lack of individual patient data precluded the analysis of time-to-event data and identification of subgroups which potentially benefit more from combination therapy such as younger patients with preserved renal function and thus at lower risk to experience worsening renal function or hyperkalemia.

Conclusions/Significance

Combination therapy with ARBs and ACE inhibitors reduces admissions for heart failure in patients with congestive heart failure when compared to ACE inhibitor therapy alone, but does not reduce overall mortality or all-cause hospitalization and is associated with more adverse events. Thus, based on current evidence, combination therapy with ARBs and ACE inhibitors may be reserved for patients who remain symptomatic on therapy with ACE inhibitors under strict monitoring for any signs of worsening renal function and/or symptomatic hypotension.     

Reassessment of the Unique Mode of Binding between Angiotensin II Type 1 Receptor and Their Blockers

While the molecular structures of angiotensin II (Ang II) type 1 (AT₁) receptor blockers (ARBs) are very similar, they are also slightly different. Although each ARB has been shown to exhibit a unique mode of binding to AT₁ receptor, different positions of the AT₁ receptor have been analyzed and computational modeling has been performed using different crystal structures for the receptor as a template and different kinds of software. Therefore, we systematically analyzed the critical positions of the AT₁ receptor, Tyr¹¹³, Tyr¹⁸⁴, Lys¹⁹⁹, His²⁵⁶ and Gln²⁵⁷ using a mutagenesis study, and subsequently performed computational modeling of the binding of ARBs to AT₁ receptor using CXCR4 receptor as a new template and a single version of software. The interactions between Tyr¹¹³ in the AT₁ receptor and the hydroxyl group of olmesartan, between Lys¹⁹⁹ and carboxyl or tetrazole groups, and between His²⁵⁶ or Gln²⁵⁷ and the tetrazole group were studied. The common structure, a tetrazole group, of most ARBs similarly bind to Lys¹⁹⁹, His²⁵⁶ and Gln²⁵⁷ of AT₁ receptor. Lys¹⁹⁹ in the AT₁ receptor binds to the carboxyl group of EXP3174, candesartan and azilsartan, whereas oxygen in the amidecarbonyl group of valsartan may bind to Lys¹⁹⁹. The benzimidazole portion of telmisartan may bind to a lipophilic pocket that includes Tyr¹¹³. On the other hand, the n-butyl group of irbesartan may bind to Tyr¹¹³. In conclusion, we confirmed that the slightly different structures of ARBs may be critical for binding to AT₁ receptor and for the formation of unique modes of binding.     

Interaction of Angiotensin I-Converting Enzyme with Two Potent Tricyclic Inhibitors

Abstract

Inhibition of rabbit lung angiotensin I-converting enzyme was studied with two inhibitors that combined tricyclic mimics of a substrate C-terminal dipeptide recognition unit with a 4-phenylbutanoic acid fragment. The overall inhibition constant for [4S-[4α,7α(R),12bB]]-7–[S-(l-carboxy-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylic acid (MDL 27,088) was approximately 4pM, whereas that for [4R-[4α,7α(S),12β]]-7–[S-(1-carboxy-3-phenylpropyl)amino]-3,4,6,7,8,12b-hexahydro-6-oxo-1H-[1,4]thiazino[3,4-a][2]benzazepine-4-carboxylic acid (MDL 27,788) was estimated to be 46 pM. The formation of an initial complex of target enzyme and MDL 27,088 and its slower isomerization to a second complex were characterized kinetically. Both compounds appear to be among the most potent inhibitors known for this enzyme.     

Anti-Inflammatory Effects of Angiotensin Receptor Blockers in the Brain and the Periphery

In addition to regulating blood pressure, Angiotensin II (Ang II) exerts powerful pro-inflammatory effects in hypertension through stimulation of its AT₁ receptors, most clearly demonstrated in peripheral arteries and in the cerebral vasculature. Administration of Ang II receptor blockers (ARBs) decreases hypertension-related vascular inflammation in peripheral organs. In rodent models of genetic hypertension, ARBs reverse the inflammation in the cerebral microcirculation. We hypothesized that ARBs could be effective in inflammatory conditions beyond hypertension. Our more recent studies, summarized here, indicate that this is indeed the case. We used the model of systemic administration of the bacterial endotoxin lipopolysaccharide (LPS). LPS produces a robust initial inflammatory reaction, the innate immune response, in peripheral organs and in the brain. Pretreatment with the ARB candesartan significantly diminishes the response to LPS, including reduction of pro-inflammatory cytokine release to the general circulation and decreased production and release of the pro-inflammatory adrenal hormone aldosterone. In addition, the ARB very significantly decreased the LPS-induced gene expression of pro-inflammatory cytokines and microglia activation in the brain. Our results demonstrate that AT₁ receptor activity is essential for the unrestricted development of full-scale innate immune response in the periphery and in the brain. ARBs, due to their immune response-limiting properties, may be considered as therapeutically useful in a number of inflammatory diseases of the peripheral organs and the brain.     

Possible Molecular Mechanisms by which Angiotensin II Type 1 Receptor Blockers (ARBs) Prevent the Development of Atrial Fibrillation in Insulin Resistant Patients

Atrial fibrillation (AF) is the most common disorder of cardiac rhythm and is responsible for substantial morbidity and mortality in general population. A recent community-based observational study revealed that diabetes and/or hypertension were associated with the development of AF. However, there is no definite evidence to show that patients with type 1 diabetes have an increased risk for the development of AF. These findings suggest that hyperglycemia per se may not explain the positive association between diabetes and AF. Growing body of evidence supports the presence of insulin resistance as the fundamental pathophysiological disturbance responsible for the metabolic syndrome, a constellation of metabolic disorders such as hypertension, dyslipidemia, and obesity that raise the risk for diabetes mellitus and cardiovascular diseases. Further, several clinical trials have shown that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of insulin resistance. These observations suggest that insulin resistance could account for the increased risk for AF in the patients with diabetes and/or hypertension and that the interruption of the RAS may be a promising therapeutic strategy for preventing the development of AF. In the first part of this paper, we review clinical studies to support the concept that angiotensin II type 1 receptor blockers (ARBs) could prevent the development of AF in insulin resistant patients and discuss the possible underlying mechanisms. In the second part, we discuss the potential utility of telmisartan, a unique ARB with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity, for blocking the development of AF in patients with insulin resistance.     

De-Intensification of Diabetes Treatment in Elderly Patients with Type 2 Diabetes Mellitus

Objective: De-intensification of diabetes treatment is recommended in elderly patients with tight glycemic control at high risk of hypoglycemia. However, rates of de-intensification in endocrine practice are unknown. We conducted a retrospective study to evaluate the rate of de-intensification of antidiabetic treatment in elderly patients with type 2 diabetes mellitus (T2DM) and tight glycemic control.Methods: All patients with ≥2 clinic visits over a 1-year period at a major academic diabetes center were included. De-intensification of diabetes treatment was defined as a decrease or discontinuation of any antidiabetic drug without adding another drug, or a reduction in the total daily dose of insulin or a sulfonylurea drug with or without adding a drug without risk of hypoglycemia.Results: Out of 3,186 unique patients, 492 were ≥65 years old with T2DM and hemoglobin A1c (HbA1c) <7.5% (<58 mmol/mol). We found 308 patients treated with a sulfonylurea drug or insulin, 102 of whom had hypoglycemia as per physician note. Among these 102 patients, 38 (37%) were advised to de-intensify therapy. In a subgroup analysis of patients ≥75 years old with HbA1c <7% (<53 mmol/mol), we found that out of 23 patients treated with a sulfonylurea drug or insulin and reporting hypoglycemia, 11 (43%) were advised de-intensification of therapy. There were no significant predictors of de-intensification of treatment.Conclusion: Our study suggests that de-intensification of antidiabetic medications is uncommon in elderly patients with T2DM. Strategies may need to be developed to prevent the potential harm of overtreatment in this population.Abbreviations: ADA = American Diabetes Association; CGM = continuous glucose monitoring; HbA1c = hemoglobin A1c; T2DM = type 2 diabetes mellitus; UKPDS = United Kingdom Prospective Diabetes Study     

Development of Contrast-Induced Acute Kidney Injury after Elective Contrast Media Exposure in Patients with Type 2 Diabetes Mellitus: Effect of Albuminuria

Background

The influence of albuminuria and urinary pH on the development of contrast-induced acute kidney disease (CI-AKI) in patients with type 2 diabetes mellitus (T2DM) after elective coronary angiography (CAG) or percutaneous coronary intervention (PCI) is unknown.

Methods

CI-AKI was defined as an increase in serum creatinine >26.4 µmol/L or ≥50% of baseline value within 48 hours after contrast media exposure. Demographics, traditional risk factors, clinical outcomes and CI-AKI incidence were compared between groups. Univariate analysis and multivariate logistic regression were performed to assess risk factors of CI-AKI.

Results

We observed 597 patients with T2DM after CAG or PCI. Patients were divided into 3 groups based on early morning urinary albumin: negative group (urine dipstick negative, n = 483), trace group (urine dipstick trace, n = 60), and positive group (urine dipstick ≥1+, n = 54). CI-AKI occurred in 33 (5.5%) patients, including 19 (3.9%) in the negativealbuminuria group, 4 (6.7%) in the trace group, and 10 (18.5%) in the positive group (p< 0.001), respectively. After adjusting for potential confounding risk factors, positive albuminuria (OR = 3.8, 95% CI: 1.5 to 9.2, p = 0.004) and urinary pH<6 (OR = 2.4, 95% CI: 1.1 to 5.1, p = 0.020) remained significantly associated with CI-AKI.

Conclusion

Preprocedural albuminuria and urinary pH <6 are independent risk factors of CI-AKI in patients with T2DM undergoing elective cardiac catheterization, and may be used to identify patients at high risk of post-procedural CI-AKI.     

The Crystal Structure of Angiotensin II Type 2 Receptor with Endogenous Peptide Hormone

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Oral Supplementation with Cholecalciferol 800 IU Ameliorates Albuminuria in Chinese Type 2 Diabetic Patients with Nephropathy

Background

Low vitamin D levels can be associated with albuminuria, and vitamin D analogs are effective anti-proteinuric agents. The aim of this study was to investigate differences in vitamin D levels between those with micro- and those with macroalbuminuria, and to determine whether low dose cholecalciferol increases vitamin D levels and ameliorates albuminuria.

Methods

Two studies were performed in which 25-OH vitamin D₃ (25(OH)D₃) concentrations were determined by electrochemiluminescence immunoassay: 1) a cross-sectional study of patients with type 2 diabetes mellitus (T2DM) (n = 481) and healthy controls (n = 78); and 2) a longitudinal study of T2DM patients with albuminuria treated with conventional doses, 800 IU, of cholecalciferol for 6 months (n = 22), and a control group (n = 24).

Results

1) Cross-sectional study: Compared to controls and T2DM patients with normoalbuminuria, serum 25(OH)D₃ concentrations were significantly lower in patients with macro-albuminuria, but not in those with micro-albuminuria. Serum 25(OH)D₃ levels were independently correlated with microalbuminuria. 2) Longitudinal study: Cholecalciferol significantly decreased microalbuminuria in the early stages of treatment, in conjunction with an increase in serum 25(OH)D₃ levels.

Conclusions

Low vitamin D levels are common in type 2 diabetic patients with albuminuria, particularly in patients with macroalbuminuria, but not in those with microalbuminuria. Conventional doses of cholecalciferol may have antiproteinuric effects on Chinese type 2 diabetic patients with nephropathy.     

Diabetic Ketoacidosis in Peruvian Patients with Type 2 Diabetes Mellitus

ObjectiveTo describe the clinical and laboratory characteristics of diabetic ketoacidosis (DKA) in adult Peruvian patients with type 2 diabetes mellitus.MethodsIn this cross-sectional analysis, we reviewed clinical charts of type 2 diabetic patients with DKA admitted to Cayetano Heredia Hospital between 2001 and 2005 for data on demographics, previous treatment, previous hospital admissions for DKA, family history of diabetes, precipitating factors, hospital course, mortality, and insulin use 3 and 6 months after the index DKA episode. Patients older than 18 years who had confirmed DKA were included. Patients with type 1 diabetes mellitus were excluded.ResultsWe report on 53 patients with DKA for whom complete clinical and laboratory data were available. Of the 53 patients, 39 (74%) were men; mean age (± SD) was 45 ± 12 years; and 22 (42%) had no previous diagnosis of type 2 diabetes. The following mean (± SD) laboratory values were obtained at DKA diagnosis: glucose, 457 ± 170 mg/dL; pH, 7.15 ± 0.14; bicarbonate, 7.73 ± 6 mEq/L; and anion gap, 24.45 ± 7.44 mEq/L. Of the 53 DKA episodes, 35 (66%) were severe (arterial pH < 7.0 and/or serum bicarbonate < 10 mEq/L). The following precipitating factors were discerned: discontinuation of treatment in 21 (40%), infections in 16 (30%), intercurrent illness in 3 (6%), and no identifiable cause in 13 (25%). Mortality rate was 0%. Three and 6 months after the index DKA episode, insulin was used by 65% and 56% of patients, respectively.ConclusionIn countries with a low incidence of type 1 diabetes, DKA is frequently reported in patients with type 2 diabetes. In this study, 42% of patients had new-onset disease. Most DKA episodes were severe and were related to infection or noncompliance with treatment. (Endocr Pract. 2008;14:442-446)     

Angiotensin Type 2 Receptor Signaling in Satellite Cells Potentiates Skeletal Muscle Regeneration

Patients with advanced congestive heart failure (CHF) or chronic kidney disease (CKD) often have increased angiotensin II (Ang II) levels and cachexia. Ang II infusion in rodents causes sustained skeletal muscle wasting and decreases muscle regenerative potential through Ang II type 1 receptor (AT1R)-mediated signaling, likely contributing to the development of cachexia in CHF and CKD. However, the potential role of Ang II type 2 receptor (AT2R) signaling in skeletal muscle physiology is unknown. We found that AT2R expression was increased robustly in regenerating skeletal muscle after cardiotoxin (CTX)-induced muscle injury in vivo and differentiating myoblasts in vitro, suggesting that the increase in AT2R played an important role in regulating myoblast differentiation and muscle regeneration. To determine the potential role of AT2R in muscle regeneration, we infused C57BL/6 mice with the AT2R antagonist PD123319 during CTX-induced muscle regeneration. PD123319 reduced the size of regenerating myofibers and expression of the myoblast differentiation markers myogenin and embryonic myosin heavy chain. On the other hand, AT2R agonist {"type":"entrez-protein","attrs":{"text":"CGP42112","term_id":"874777115","term_text":"CGP42112"}}CGP42112 infusion potentiated CTX injury-induced myogenin and embryonic myosin heavy chain expression and increased the size of regenerating myofibers. In cultured myoblasts, AT2R knockdown by siRNA suppressed myoblast differentiation marker expression and myoblast differentiation via up-regulation of phospho-ERK1/2, and ERK inhibitor treatment completely blocked the effect of AT2R knockdown. These data indicate that AT2R signaling positively regulates myoblast differentiation and potentiates skeletal muscle regenerative potential, providing a new therapeutic target in wasting disorders such as CHF and CKD.