Epoxide hydrolase and epoxygenase metabolites as therapeutic targets for renal diseases

2005 ◽  
Vol 289 (3) ◽  
pp. F496-F503 ◽  
Author(s):  
John D. Imig
Keyword(s):  
Cardiovascular Diseases ◽  
Epoxide Hydrolase ◽  
Pressure Control ◽  
Organ Damage ◽  
Renal Diseases ◽  
Epoxyeicosatrienoic Acid ◽  
Protective Actions ◽  
Antihypertensive Properties ◽  
Cytochrome P 450

Renal epoxygenase metabolites are involved in blood flow regulation and long-term blood pressure control. One feature of renal and cardiovascular diseases is the inability of the kidney to properly increase epoxyeicosatrienoic acid (EET) levels. Others (Busse R, Edwards G, Félétou M, Fleming I, Vanhoutte PM, and Weston AH. Trends Phamacol Sci 23: 374–380, 2002; Campbell WB, Gebremedhin D, Pratt PF, and Harder DR. Circ Res 78: 415–423, 1996; Capdevila JH and Falck JR. Biochem Biophys Res Commun 285: 571–576, 2001; Roman RJ. Physiol Rev 82: 131–185, 2002; Zeldin DC. J Biol Chem 276: 36059–36062, 2001) and we (Imig JD, Falck JR, Wei S, and Capdevila JH. J Vasc Res 38: 247–255, 2001; Imig JD, Zhao X, Capdevila JH, Morisseau C, and Hammock BD. Hypertension 39: 690–694, 2002; Zhao X, Pollock DM, Inscho EW, Zeldin DC, and Imig JD. Hypertension 41: 709–714, 2003; Zhao X, Pollock DM, Zeldin DC, and Imig JD. Hypertension 42: 775–780, 2003) have provided compelling evidence that cytochrome P-450-derived EETs have antihypertensive properties and are endothelially derived hyperpolarizing factors (EDHFs) in the kidney. EETs also possess anti-inflammatory actions that could protect the kidney vasculature from injury during renal and cardiovascular diseases. A tactic that has been used to increase EET levels has been inhibition of the soluble epoxide hydrolase enzyme. Epoxide hydrolase inhibitors have been demonstrated to be antihypertensive and renal protective. Thus the renal and cardiovascular protective actions of increasing epoxygenase levels could be translated to therapies for preventing end-organ damage.

scholarly journals Atrial Natriuretic Peptide31–67: A Novel Therapeutic Factor for Cardiovascular Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Gustavo Jose Justo da Silva ◽  
Raffaele Altara ◽  
George W. Booz ◽  
Alessandro Cataliotti
Keyword(s):  
Therapeutic Strategy ◽  
Mechanical Stretch ◽  
Organ Damage ◽  
Renal Diseases ◽  
Preclinical Models ◽  
Endocrine Organ ◽  
Protective Actions ◽  
Main Effects ◽  
Atrial Natriuretic

The characterization of the cardiac hormone atrial natriuretic peptide (ANP99–126), synthesized and secreted predominantly by atrial myocytes under stimulation by mechanical stretch, has established the heart as an endocrine organ with potent natriuretic, diuretic, and vasodilating actions. Three additional distinct polypeptides resulting from proteolytic cleavage of proANP have been identified in the circulation in humans. The mid-sequence proANP fragment 31–67 (also known as proANP31–67) has unique potent and prolonged diuretic and natriuretic properties. In this review, we report the main effects of this circulating hormone in different tissues and organs, and its mechanisms of actions. We further highlight recent evidence on the cardiorenal protective actions of chronic supplementation of synthetic proANP31–67 in preclinical models of cardiorenal disease. Finally, we evaluate the use of proANP31–67 as a new therapeutic strategy to repair end-organ damage secondary to hypertension, diabetes mellitus, renal diseases, obesity, heart failure, and other morbidities that can lead to impaired cardiac function and structure.

scholarly journals Long-Term Renal Outcomes in Hereditary TTP Patients: Data from the International Hereditary TTP Registry

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 770-770
Author(s):  
Erika Tarasco ◽  
Ralph Wendt ◽  
Anne Sophie von Krogh ◽  
Sibylle Tschumi ◽  
James N. George ◽  
...  
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Kidney Disease ◽  
Renal Disease ◽  
Organ Damage ◽  
Renal Diseases ◽  
Compound Heterozygous ◽  
Advisory Committees ◽  
Ckd Stage

Abstract Introduction Hereditary thrombotic thrombocytopenic purpura (hTTP) is an ultra-rare thrombotic microangiopathy caused by autosomal recessively inherited severe ADAMTS13 deficiency. In respect to organ damage, we recently reported a heterogeneous clinical course with some patients having various degrees of organ damage while others are almost asymptomatic*. The long-term consequences of hTTP are still not fully known. Methods We analyzed the prevalence and development of renal disease in confirmed hTTP patients in the International Hereditary TTP Registry until July 2021. We studied the onset of kidney disease, the presence of additional co-morbidities and the possibility of a specific genotype-phenotype correlation. We classified different renal diseases of our hTTP patients, according to the ICD-10 code (version 2016) as described in Table 1. Results Thirty-five (21%) of 163 confirmed hTTP patients of the International TTP Registry with a mean age at enrolment of 38.2 years had kidney disease. 80% were Caucasian, 8.5% Asian and 11.5% indicated other ethnicities. According to the ICD-10 code classification, two patients had acute kidney disease (AKI, ICD code N17) not specified during acute TTP episodes. Among 18 patients with general CKD, we could identified three patients with chronic kidney disease (CKD, ICD code N18) stages 1-2; four with CKD stage 3, and four patient with CKD stage 5. In two patients, kidney disease was unspecified (ICD code N19). Five patients had diagnoses of certain specific renal diseases, such as acute glomerulonephritis (ICD code N00), unspecified nephritis syndrome (ICD code N05), recurrent and persistent hematuria (ICD code N02), and calculus of the kidney (ICD code N20) (Table 1). Seven patients developed end-stage renal disease requiring renal replacement therapy (ICD code Z99.2), which was temporarily needed in four additional patients (Z49.2). Two patients underwent kidney transplantation (ICD code Z94) (Table 1). The 163 hTTP patients experienced 625 acute disease episodes, of which 108 (17%) were associated with acute renal failure. 21/163 (13%) acute episodes were treated with hemodialysis. After experiencing several hTTP episodes with acute renal failure, 15 patients developed CKD at different stages. 26/35 (74%) hTTP patients with kidney disease presented also other co-morbidities: hypertension in 14 patients, 10 and 18 patients had suffered from transient ischemic attacks and/or strokes, and six patients had suffered from a myocardial infarction. We observed no apparent correlation between onset of CKD and presence of co-morbidities. Regular plasma prophylaxis was introduced in 26/35 hTTP patients with kidney disease; in the majority of them (64%) plasma treatment was started due to CKD or after CKD diagnosis. Of the 35 patients with renal disease, 15 were homozygous and 20 compound heterozygous ADAMTS13 mutation carriers. The most known ADAMTS13 mutation c.4143_4144dupA counts 33% of the whole hTTP patients in our database (54/163 patients). It was the most represented mutations in our cohort of hTTP patients with renal disease (60%, 21/35): 11 homozygous and 10 compound heterozygous carriers. Nevertheless, we did not observe a specific genotype-phenotype correlation. Conclusions Our analysis of the International Hereditary TTP Registry cohort (at present 163 patients) showed that the majority of patients had a diagnosis of hTTP before a diagnosis of kidney disease, especially CKD. We could not identify a correlation with the onset of additional co-morbidities or with the genotype; nevertheless we cannot exclude that it may be present. Considering that 43% (15/35) patients developed CKD after several acute episodes with acute renal failure, a closer and attentive care for those patients not yet developing CKD to avoid or delay the onset is highly recommended. Hence, to evaluate the contribution of acute hTTP episodes and of other co-morbidities to the development of kidney disease requires further in depth analyses. More frequent and long-term follow-up visits are needed to better understand the long-term outcome and development of kidney disease in hTTP patients. * Tarasco et al, Blood 2021 Figure 1 Figure 1. Disclosures Matsumoto: Sanofi: Consultancy; Takeda: Consultancy; Alexion Pharma: Consultancy; Asahi Kasei Pharma: Research Funding; Chugai Pharmaceutical: Research Funding; Alfesa Pharma: Patents & Royalties: ELISA for measuring ADAMTS13 activity. Lämmle: Takeda: Membership on an entity's Board of Directors or advisory committees; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Baxter: Other: Travel Support, Speakers Bureau; Alexion: Other: Travel Support, Speakers Bureau; Siemens: Other: Travel Support, Speakers Bureau; Bayer: Other: Travel Support, Speakers Bureau; Roche: Other: Travel Support, Speakers Bureau; Sanofi: Other: Travel Support, Speakers Bureau. Kremer Hovinga Strebel: Baxalta US Inc: Other: grant; Shire: Consultancy, Speakers Bureau; Ablynx: Consultancy, Speakers Bureau; Federal Office of Public Health: Consultancy; Insel Gruppe AG: Current Employment.

scholarly journals Blood Pressure Variability and Risk for Progression of Cardiovascular and Renal Diseases in Patients with Diabetes Mellitus

2015 ◽  
Vol 22 (3) ◽  
pp. 297-304 ◽  
Author(s):  
Sorin Ioan Zaharie ◽  
Teodora Daniela Maria ◽  
Mirela Zaharie ◽  
Maria Moţa ◽  
Eugen Moţa
Keyword(s):  
Diabetes Mellitus ◽  
Blood Pressure ◽  
Cardiovascular Events ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Renal Diseases ◽  
Hypertensive Patients ◽  
Patients With Diabetes ◽  
Prognostic Importance

Abstract Accurate measurement of blood pressure (BP) and evaluation of global cardiovascular risk is crucial for diagnosis and treatment of hypertensive patients. When hypertension and diabetes mellitus are associated, the risk for cardiovascular events is bigger than the sum of the components. Beyond systolic and diastolic BP values as targets for antihypertensive treatment, recent guidelines recognize BP variability as an independent predictor for future cardiovascular events. 24 hours ambulatory BP monitoring (ABPM) and home BP monitoring (HBPM) are two methods used in patient day to day life conditions for BP measurements. Increased variability of systolic and/or diastolic BP within one day (“short-term BP variability”) and also over longer periods (“long-term BP variability”) showed by ABPM and/or HBPM is associated with target-organ damage and cardiovascular events. This review is focused on the prognostic importance of BP variability in hypertensive patients with diabetes mellitus.

scholarly journals Weight-Loss Strategies for Prevention and Treatment of Hypertension: A Scientific Statement From the American Heart Association

Hypertension ◽  
2021 ◽  
Author(s):  
Michael E. Hall ◽  
Jordana B. Cohen ◽  
Jamy D. Ard ◽  
Brent M. Egan ◽  
John E. Hall ◽  
...  
Keyword(s):  
Weight Loss ◽  
Lifestyle Modification ◽  
Kidney Diseases ◽  
Target Organ Damage ◽  
Heart Association ◽  
Organ Damage ◽  
The United States ◽  
Target Organ ◽  
Renal Diseases

Hypertension is a major risk factor for cardiovascular and renal diseases in the United States and worldwide. Obesity accounts for much of the risk for primary hypertension through several mechanisms, including neurohormonal activation, inflammation, and kidney dysfunction. As the prevalence of obesity continues to increase, hypertension and associated cardiorenal diseases will also increase unless more effective strategies to prevent and treat obesity are developed. Lifestyle modification, including diet, reduced sedentariness, and increased physical activity, is usually recommended for patients with obesity; however, the long-term success of these strategies for reducing adiposity, maintaining weight loss, and reducing blood pressure has been limited. Effective pharmacotherapeutic and procedural strategies, including metabolic surgeries, are additional options to treat obesity and prevent or attenuate obesity hypertension, target organ damage, and subsequent disease. Medications can be useful for short- and long-term obesity treatment; however, prescription of these drugs is limited. Metabolic surgery is effective for producing sustained weight loss and for treating hypertension and metabolic disorders in many patients with severe obesity. Unanswered questions remain related to the mechanisms of obesity-related diseases, long-term efficacy of different treatment and prevention strategies, and timing of these interventions to prevent obesity and hypertension-mediated target organ damage. Further investigation, including randomized controlled trials, is essential to addressing these questions, and emphasis should be placed on the prevention of obesity to reduce the burden of hypertensive cardiovascular and kidney diseases and subsequent mortality.

scholarly journals Soluble epoxide hydrolase contamination of specific catalase preparations inhibits epoxyeicosatrienoic acid vasodilation of rat renal arterioles

2011 ◽  
Vol 301 (4) ◽  
pp. F765-F772 ◽  
Author(s):  
Kathryn M. Gauthier ◽  
Lauren Olson ◽  
Adam Harder ◽  
Marilyn Isbell ◽  
John D. Imig ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
Bovine Liver ◽  
Soluble Epoxide Hydrolase ◽  
Spectrometric Analysis ◽  
Peptide Fragments ◽  
Epoxyeicosatrienoic Acid ◽  
Vascular Activity ◽  
Afferent Arterioles ◽  
Hydrolysis Of ◽  
Cytochrome P 450

Cytochrome P-450 metabolites of arachidonic acid, the epoxyeicosatrienoic acids (EETs) and hydrogen peroxide (H2O2), are important signaling molecules in the kidney. In renal arteries, EETs cause vasodilation whereas H2O2 causes vasoconstriction. To determine the physiological contribution of H2O2, catalase is used to inactivate H2O2. However, the consequence of catalase action on EET vascular activity has not been determined. In rat renal afferent arterioles, 14,15-EET caused concentration-related dilations that were inhibited by Sigma bovine liver (SBL) catalase (1,000 U/ml) but not Calbiochem bovine liver (CBL) catalase (1,000 U/ml). SBL catalase inhibition was reversed by the soluble epoxide hydrolase (sEH) inhibitor tAUCB (1 μM). In 14,15-EET incubations, SBL catalase caused a concentration-related increase in a polar metabolite. Using mass spectrometry, the metabolite was identified as 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), the inactive sEH metabolite. 14,15-EET hydrolysis was not altered by the catalase inhibitor 3-amino-1,2,4-triazole (3-ATZ; 10–50 mM), but was abolished by the sEH inhibitor BIRD-0826 (1–10 μM). SBL catalase EET hydrolysis showed a regioisomer preference with greatest hydrolysis of 14,15-EET followed by 11,12-, 8,9- and 5,6-EET ( Vmax = 0.54 ± 0.07, 0.23 ± 0.06, 0.18 ± 0.01 and 0.08 ± 0.02 ng DHET·U catalase−1·min−1, respectively). Of five different catalase preparations assayed, EET hydrolysis was observed with two Sigma liver catalases. These preparations had low specific catalase activity and positive sEH expression. Mass spectrometric analysis of the SBL catalase identified peptide fragments matching bovine sEH. Collectively, these data indicate that catalase does not affect EET-mediated dilation of renal arterioles. However, some commercial catalase preparations are contaminated with sEH, and these contaminated preparations diminish the biological activity of H2O2 and EETs.

scholarly journals Epoxide hydrolases regulate epoxyeicosatrienoic acid incorporation into coronary endothelial phospholipids

1999 ◽  
Vol 277 (5) ◽  
pp. H2098-H2108 ◽  
Author(s):  
Neal L. Weintraub ◽  
Xiang Fang ◽  
Terry L. Kaduce ◽  
Mike VanRollins ◽  
Papri Chatterjee ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Epoxide Hydrolase ◽  
Epoxyeicosatrienoic Acids ◽  
Epoxyeicosatrienoic Acid ◽  
Epoxide Hydrolases ◽  
Porcine Coronary Artery ◽  
A 23187 ◽  
Acid Incorporation ◽  
Cytochrome P 450 ◽  
Endothelium Dependent Relaxation

Cytochrome P-450-derived epoxyeicosatrienoic acids (EETs) are avidly incorporated into and released from endothelial phospholipids, a process that results in potentiation of endothelium-dependent relaxation. EETs are also rapidly converted by epoxide hydrolases to dihydroxyeicosatrienoic acid (DHETs), which are incorporated into phospholipids to a lesser extent than EETs. We hypothesized that epoxide hydrolases functionally regulate EET incorporation into endothelial phospholipids. Porcine coronary artery endothelial cells were treated with an epoxide hydrolase inhibitor, 4-phenylchalcone oxide (4-PCO, 20 μmol/l), before being incubated with 3H-labeled 14,15-EET (14,15-[3H]EET). 4-PCO blocked conversion of 14,15-[3H]EET to 14,15-[3H]DHET and doubled the amount of radiolabeled products incorporated into cell lipids, with >80% contained in phospholipids. Moreover, pretreatment with 4-PCO before incubation with 14,15-[3H]EET enhanced A-23187-induced release of radiolabeled products into the medium. In contrast, 4-PCO did not alter uptake, distribution, or release of [3H]arachidonic acid. In porcine coronary arteries, 4-PCO augmented 14,15-EET-induced potentiation of endothelium-dependent relaxation to bradykinin. These data suggest that epoxide hydrolases may play a role in regulating EET incorporation into phospholipids, thereby modulating endothelial function in the coronary vasculature.

scholarly journals Understanding sex differences in long-term blood pressure regulation: insights from experimental studies and computational modeling

2019 ◽  
Vol 316 (5) ◽  
pp. H1113-H1123 ◽  
Author(s):  
Sameed Ahmed ◽  
Rui Hu ◽  
Jessica Leete ◽  
Anita T. Layton
Keyword(s):  
Blood Pressure ◽  
Sex Differences ◽  
Computational Models ◽  
Experimental Studies ◽  
Pressure Control ◽  
Blood Pressure Regulation ◽  
Pressure Regulation ◽  
Physiological Processes ◽  
Key Players

Sex differences in blood pressure and the prevalence of hypertension are found in humans and animal models. Moreover, there has been a recent explosion of data concerning sex differences in nitric oxide, the renin-angiotensin-aldosterone system, inflammation, and kidney function. These data have the potential to reveal the mechanisms underlying male-female differences in blood pressure control. To elucidate the interactions among the multitude of physiological processes involved, one may apply computational models. In this review, we describe published computational models that represent key players in blood pressure regulation, and highlight sex-specific models and their findings.

scholarly journals A case of hypereosinophilic syndrome with STAT5b N642H mutation

2021 ◽  
Vol 2021 (1) ◽  
Author(s):  
Feihong Ding ◽  
Chaoping Wu ◽  
Yun Li ◽  
Sudipto Mukherjee ◽  
Subha Ghosh ◽  
...  
Keyword(s):  
Complete Blood Count ◽  
Hypereosinophilic Syndrome ◽  
Organ Damage ◽  
Myeloid Neoplasm ◽  
Acute Eosinophilic Pneumonia ◽  
Myeloid Neoplasms ◽  
Somatic Signal ◽  
Generation Sequencing

ABSTRACT Hypereosinophilia is defined as persistent eosinophilia (>1.5 × 109/L). Hypereosinophilic syndrome (HES) is a term used to describe a group of disorders characterized by sustained hypereosinophilia associated with end-organ damage. Based on underlying molecular mechanism of eosinophilia, there are different subtypes of HES. Diagnosis of HES subtype can be challenging, especially in the absence of overt lymphoid/myeloid neoplasms or discernable secondary causes. Long-term outpatient follow-up with periodic complete blood count and repeated bone marrow biopsy may be needed to monitor disease activity. Somatic signal transducer and activation transcription 5b (STAT5b) N642H mutation was recently found to be associated with myeloid neoplasms with eosinophilia. We report a case of HES who presented with pulmonary embolism and acute eosinophilic pneumonia, found to have recurrent STAT5b N642H mutation by next-generation sequencing, suggesting possible underlying myeloid neoplasm.

scholarly journals POS0815 CLINICAL CHARACTERISTICS, IMAGING PHENOTYPE, AND LONG-TERM OUTCOMES OF TAKAYASU ARTERITIS PATIENTS WITH HYPERTENSION

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 661.1-661
Author(s):  
Y. Sun ◽  
L. Ma ◽  
H. Chen ◽  
C. Rongyi ◽  
L. Jiang
Keyword(s):  
Blood Pressure ◽  
Adverse Events ◽  
Clinical Features ◽  
Takayasu Arteritis ◽  
Pressure Control ◽  
Free Survival ◽  
The World ◽  
Cluster 2

Background:Hypertension occurred in 30-80% of TAK patients around the world. The occurrence of hypertension might severely worsen TAK prognosis. Nevertheless, data describing the specific imaging features in hypertensive TAK patients and the associations between hypertensive severity, blood pressure control status and long-term outcome were still lacking.Objectives:To investigate the characteristics and associations of hypertensive characteristics with adverse events-free survival in Takayasu arteritis (TAK) patients with hypertension.Methods:This research was based on a prospectively on-going observational cohort-East China Takayasu Arteritis (ECTA) cohort. In all, 618 TAK patients, who registered in the ECTA cohort up to December 2019, were enrolled. The main outcome was the adverse-events-free survival among hypertensive TAK patients during the follow-up ended on August 2020.Results:Totally, 204 (33.0%) patients suffered from hypertension, with 48 (23.5%), 62 (30.4%), and 94 (46.1%) mild, moderate, and severe hypertension, respectively. Cluster analysis indicated three imaging phenotypes for hypertensive TAK patients: Cluster 1: involvement of the abdominal aorta and/or renal artery (n=56, 27.5%); Cluster 2: involvement of the ascending aorta, thoracic aorta, and the aortic arch and its branches (n=38, 18.6%); Cluster 3: combined involvement of Cluster 1 and Cluster 2 (n=111, 54.4%). By the end of the follow-up, the blood pressure control rate was 50.8%, while the adverse-events-free survival was 67.9% in the entire hypertensive population. Multivariate Cox regression analysis indicated that well-controlled blood pressure (HR=2.13, 95%CI 1.32–3.78, p=0.047), co-existence of severe aortic valve regurgitation (HR=0.87, 95%CI 0.64–0.95, p=0.043), Cluster 1 (HR=0.69, 95%CI 0.48–0.92, p=0.017) and Cluster 3 (HR=0.72, 95%CI 0.43–0.94, p=0.048) imaging phenotype was associated with the adverse-events-free survival.Conclusion:Patients with controlled hypertension showed better adverse-events-free survival, while those with the Cluster 1 imaging phenotype were more likely to suffer from worse adverse-events-free survival. Hypertension occurred in 30-80% of TAK patients around the world. The occurrence of hypertension might severely worsen TAK prognosis.References:[1]Johnston SL, Lock RJ, Gompels MM. Takayasu arteritis: a review. J Clin Pathol 2002; 55:481–6.[2]Watanabe Y, Miyata T, Tanemoto K. Current clinical features of new patients with Takayasu arteritis observed from a cross-country research in Japan: age and sex specificity. Circulation 2015; 132:1701–9.[3]Yilmaz N, Can M, Oner FA, et al. Impaired quality of life, disability and mental health in Takayasu’s arteritis. Rheumatol. (Oxford) 2013; 52:1898–904.[4]Laurent A, Julien H, Nicolas L, et al. Takayasu arteritis in France: a single-center retrospective study of 82 cases comparing white, North African, and black patients. Medicine 2010; 89:1–17.[5]Mwipatayi BP, Jeffery PC, Beningfield SJ, et al. Takayasu arteritis: clinical features and management: report of 272 cases. ANZ J Surg 2005; 75:110–7.Disclosure of Interests:None declared

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