MicroRNAs mediate the cardioprotective effect of angiotensin-converting enzyme inhibition in acute kidney injury

2015 ◽  
Vol 309 (11) ◽  
pp. F943-F954 ◽  
Author(s):  
Indrajeetsinh Rana ◽  
Elena Velkoska ◽  
Sheila K. Patel ◽  
Louise M. Burrell ◽  
Fadi J. Charchar
Keyword(s):  
Kidney Disease ◽  
Angiotensin Converting Enzyme ◽  
Cardiac Hypertrophy ◽  
Inhibitory Action ◽  
Target Genes ◽  
Ace Inhibitor ◽  
Kidney Injury ◽  
Converting Enzyme ◽  
Subtotal Nephrectomy ◽  
Inhibitor Treatment

Cardiovascular disease, including cardiac hypertrophy, is common in patients with kidney disease and can be partially attenuated using blockers of the renin-angiotensin system (RAS). It is unknown whether cardiac microRNAs contribute to the pathogenesis of cardiac hypertrophy or to the protective effect of RAS blockade in kidney disease. Using a subtotal nephrectomy rat model of kidney injury, we investigated changes in cardiac microRNAs that are known to have direct target genes involved in the regulation of apoptosis, fibrosis, and hypertrophy. The effect of treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril on cardiac microRNAs was also investigated. Kidney injury led to a significant increase in cardiac microRNA-212 and microRNA-132 expression. Ramipril reduced cardiac hypertrophy, attenuated the increase in microRNA-212 and microRNA-132, and significantly increased microRNA-133 and microRNA-1 expression. There was altered expression of caspase-9, B cell lymphoma-2, transforming growth factor-β, fibronectin 1, collagen type 1A1, and forkhead box protein O3, which are all known to be involved in the regulation of apoptosis, fibrosis, and hypertrophy in cardiac cells while being targets for the above microRNAs. ACE inhibitor treatment increased expression of microRNA-133 and microRNA-1. The inhibitory action of ACE inhibitor treatment on increased cardiac NADPH oxidase isoform 1 expression after subtotal nephrectomy surgery suggests that inhibition of oxidative stress is also one of mechanism of ACE inhibitor-mediated cardioprotection. These finding suggests the involvement of microRNAs in the cardioprotective action of ACE inhibition in acute renal injury, which is mediated through an inhibitory action on profibrotic and proapoptotic target genes and stimulatory action on antihypertrophic and antiapoptotic target genes.

scholarly journals Acute Kidney Injury in Patients Receiving Systemic Treatment for Cancer: A Population-Based Cohort Study

2018 ◽  
Vol 111 (7) ◽  
pp. 727-736 ◽  
Author(s):  
Abhijat Kitchlu ◽  
Eric McArthur ◽  
Eitan Amir ◽  
Christopher M Booth ◽  
Rinku Sutradhar ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Angiotensin Converting Enzyme ◽  
Systemic Therapy ◽  
Kidney Injury ◽  
Population Based ◽  
Converting Enzyme ◽  
Angiotensin Receptor ◽  
Increased Risk

Abstract Background Patients undergoing treatment for cancer are at increased risk of acute kidney injury (AKI). There are few data on AKI incidence and risk factors in the current era of cancer treatment. Methods We conducted a population-based study of all patients initiating systemic therapy (chemotherapy or targeted agents) for a new cancer diagnosis in Ontario, Canada (2007–2014). The primary outcome was hospitalization with AKI or acute dialysis. We estimated the cumulative incidence of AKI and fitted Fine and Gray models, adjusting for demographics, cancer characteristics, comorbidities, and coprescriptions. We modeled exposure to systemic therapy (the 90-day period following treatments) as a time-varying covariate. We also assessed temporal trends in annual AKI incidence. Results We identified 163 071 patients initiating systemic therapy of whom 10 880 experienced AKI. The rate of AKI was 27 per 1000 person-years, with overall cumulative incidence of 9.3% (95% CI = 9.1% to 9.6%). Malignancies with the highest 5-year AKI incidence were myeloma (26.0%, 95% CI = 24.4% to 27.7%), bladder (19.0%, 95% CI = 17.6% to 20.5%), and leukemia (15.4%, 95% CI = 14.3% to 16.5%). Advanced cancer stage, chronic kidney disease, and diabetes were associated with increased risk of AKI (adjusted hazard ratios [aHR] = 1.41, 95% CI = 1.28 to 1.54; 1.80, 95% CI = 1.67 to 1.93; and 1.43, 95% CI = 1.37 to 1.50, respectively). In patients aged 66 years or older with universal drug benefits, diuretic, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker coprescription was associated with higher AKI risk (aHR = 1.20, 95% CI = 1.14 to 1.28; 1.30, 95% CI = 1.23 to 1.38). AKI risk was further accentuated during the 90-day period following systemic therapy (aHR = 2.34, 95% CI = 2.24 to 2.45). The annual incidence of AKI increased from 18 to 52 per 1000 person-years between 2007 and 2014. Conclusion Cancer-related AKI is common and associated with advanced stage, chronic kidney disease, diabetes, and concomitant receipt of diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Risk is heightened in the 90 days after systemic therapy. Preventive strategies are needed to address the increasing burden of AKI in this population.

Partial escape of angiotensin converting enzyme (ACE) inhibition during prolonged ACE inhibitor treatment

1992 ◽  
Vol 10 (8) ◽  
pp. 15 ◽  
Author(s):  
Anton H. van den Meiracker ◽  
Arie J. Man in??t Veld ◽  
Peter J.J. Admiraal ◽  
Henk J. Ritsema van Eck ◽  
Frans Boomsma ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Ace Inhibitor ◽  
Ace Inhibition ◽  
Converting Enzyme ◽  
Inhibitor Treatment

Tissue Expression of Components of the Renin—Angiotensin System in Experimental Post-Infarction Heart Failure in Rats: Effects of Heart Failure and Angiotensin-Converting Enzyme Inhibitor Treatment

1997 ◽  
Vol 92 (5) ◽  
pp. 455-465 ◽  
Author(s):  
Martin P. Kelly ◽  
OLE Kahr ◽  
Christian Aalkjaer ◽  
Frederic Cumin ◽  
Nilesh J Samani
Keyword(s):  
Heart Failure ◽  
Angiotensin Converting Enzyme ◽  
Ace Inhibitor ◽  
Mrna Level ◽  
Renin Angiotensin System ◽  
Mrna Levels ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Inhibitor Treatment

1. It has been suggested that local tissue renin—angiotensin systems may be activated in heart failure and that effects on such systems may, at least partially, explain the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in this syndrome. To investigate these hypotheses, we examined expression of renin-angiotensin system components in several tissues in a rodent model of post-myocardial infarction (MI) heart failure, and analysed whether such expression is modified by ACE inhibitor treatment. 2. Four groups of rats (n = 8–12 per group) were studied 30 days after surgery: (A) sham-operated rats with no treatment, (B) rats with post-MI heart failure induced by ligation of the left coronary artery, (C) sham-operated rats treated with the ACE inhibitor perindopril (1.5 mg day−1 kg−1), and (D) rats as per B, but treated with perindopril. Expression of renin, angiotensinogen, ACE and angiotensin subtype 1 receptor was assessed by quantification of their respective mRNAs by Northern blotting. 3. Renal renin mRNA increased 2-fold in animals with MI (group B) compared with controls (group A) (P < 0.05) and between 50 and 100-fold after ACE inhibitor treatment (P < 0.001). No change in renin gene expression was found in any extra-renal site either following MI or after ACE inhibitor treatment. Hepatic angiotensinogen mRNA level was similar in all groups, but kidney angiotensinogen mRNA level was increased 1.6-fold (P < 0.01) in the groups receiving perindopril. ACE mRNA level in the lung was not affected by ACE inhibitor treatment but decreased by 50% following MI (groups B and D, P < 0.01). This was associated with a similar (50%, P < 0.01) fall in lung ACE activity and was correlated with the severity of heart failure. Angiotensin subtype 1 receptor mRNA level was not affected in any tissue by either MI or ACE inhibitor treatment. 4. We did not find a systematic activation of tissue renin-angiotensin systems, as assessed by steady-state mRNA levels of key components of the system in experimental post-MI heart failure, or a major effect of ACE inhibitor treatment on expression of these components. However, we observed tissue-specific changes in expression of selected components of the renin-angiotensin system in the kidney and the lung in post-MI heart failure and after ACE inhibitor treatment, which may be of relevance to the pathophysiology of the syndrome and the effects of ACE inhibition.

scholarly journals The Level of hs-CRP in Coronary Artery Ectasia and Its Response to Statin and Angiotensin-Converting Enzyme Inhibitor Treatment

2007 ◽  
Vol 2007 ◽  
pp. 1-4 ◽  
Author(s):  
Yilmaz Ozbay ◽  
Mehmet Akbulut ◽  
Mehmet Balin ◽  
Hidayet Kayancicek ◽  
Adil Baydas ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Angiotensin Converting Enzyme ◽  
Ace Inhibitor ◽  
Enzyme Inhibitor ◽  
Inflammatory Marker ◽  
Converting Enzyme ◽  
Coronary Artery Ectasia ◽  
Increased Risk ◽  
Hs Crp ◽  
Inhibitor Treatment

Background/Aim. Coronary artery ectasia (CAE) was thought of as a variant of atherosclerosis. C-reactive protein (CRP) which is among the most sensitive markers of systemic inflammation, and elevation of systemic and local levels of this inflammatory marker which has been associated with an increased risk for cardiovascular disease in the obstructive coronary artery disease (O-CAD) are well known, but little was known in CAE. The anti-inflammatory effects of statins and the effect of angiotensin-converting enzyme (ACE) inhibitors on endothelial dysfunction are well established in atherosclerosis. The aim of the present study was to investigate CRP level and its response to statin and ACE inhibitor treatment in CAE.Materials and method. We measured serum hs-CRP level in 40 CAE (26 males, mean age:56.32±9years) and 41 O-CAD (34 males, mean age:57.19±10years) patients referred for elective coronary angiography at baseline and after 3-month statin and ACE inhibitor treatment.Results. Plasma hs-CRP levels were significantly higher in CAE group than O-CAD group at baseline (2.68±66mg/L versus1,64±64, resp.,P<.0001). Plasma hs-CRP levels significantly decreased from baseline 3 months later in the CE (from2.68±0.66mg/L to1.2±0.53mg/L,P<.0001) as well as in the O-CAD group (from1.64±0.64mg/L to1.01±0.56mg/L, P<.001).Conclusion. We think that hs-CRP measurement may be a good prognostic value in CAE patients as in stenotic ones. Further placebo-controlled studies are needed to evaluate the clinical significance of this decrease in hs-CRP.

Abstract 17481: MicroRNAs Mediate the Protective Effect of Angiotensin Converting Enzyme Inhibition (ACEi) on the Heart in Rat Model of Acute Kidney Injury

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Indrajeet Rana ◽  
Elena Velkoska ◽  
Louise M Burrell ◽  
Fadi J Charchar
Keyword(s):  
Acute Kidney Injury ◽  
Left Ventricular Hypertrophy ◽  
Angiotensin Converting Enzyme ◽  
Cardiac Hypertrophy ◽  
Rat Model ◽  
Renal Injury ◽  
Ventricular Hypertrophy ◽  
Kidney Injury ◽  
Left Ventricular ◽  
Converting Enzyme

Introduction: Cardiovascular complications are common in patients with kidney disease. MicroRNAs play an important role in regulating cell death pathways and cardiac hypertrophy but it is not known whether cardiac microRNAs contribute to cardio-renal cross talk. microRNA-1 and microRNA-133 are associated with cardiac fibrosis and apoptosis after myocardial infarction, whilst microRNA-212/132 is associated with cardiac hypertrophy. Aim: Using a rat model we investigated whether acute kidney injury leads to changes in cardiac microRNAs (1,133,212 and 132) and their gene targets. We also tested the effect of treatment with the angiotensin converting enzyme inhibitor (ACEi) ramipril on these cardiac microRNAs. Methods: Heart tissues were collected from rats 10 days after subtotal nephrectomy (STNx) surgery, where one kidney was removed and the other partially ligated (n=9), from sham animals (n=9), and from STNx rats treated with ramipril (n=9). RNA was extracted from the left ventricle and quantitative real time PCR was used to measure microRNA and their target gene expression levels. Results: In rats with renal injury, there was a significant increase in left ventricular hypertrophy (P<0.05 vs sham). There was also a significant increase in expression of cardiac microRNA-212 (2 fold, P<0.05 vs Sham) and microRNA-132 (3 fold, P<0.05 vs Sham). Ramipril treatment in STNx rats attenuated the increase in microRNA-212 and caused a significant increase in expression of microRNA-133 (P<0.001 vs Sham, P<0.001 vs STNx+Veh) and microRNA-1 (P<0.01 vs Sham, P<0.01 vs STNx+Veh). Renal injury induced left ventricular hypertrophy was attenuated in ramipril treated STNx rats (P<0.001 vs STNx+Veh). We also found altered expression of caspase 9, fibronectin 1, collagen 1A1 and forkhead box O3, all known for their involvement in the regulation of apoptosis, fibrosis and hypertrophy in cardiac cells, whilst being targets for the above microRNAs. Conclusions: The involvement of microRNAs in cardiac pathologies associated with kidney injury is a novel finding of our study. Our finding suggests an involvement of microRNA-1, microRNA-133 and microRNA-212/132 in the cardioprotective action of ACE inhibition in acute kidney injury.

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