Angiotensin II Induces DNA Damage in the Kidney

Schmid, Ursula; Stopper, Helga; Schweda, Frank; Queisser, Nina; Schupp, Nicole

doi:10.1158/0008-5472.can-08-1310

Cited by 48 publications

(45 citation statements)

References 49 publications

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“…However, other protective possible mechanism of actions for the ACE inhibitor, enalapril, includes its ability to block angiotensin II-dependent activation of proinflammatory and prooxidant pathways which may be earlier events through the profibrotic ones and inflammation (Cozzoli et al 2011). It is worth mentioning that Ang II induced DNA damage in the mouse kidney (Schmid et al 2008). Taking all these together, it can be speculated that the ACE inhibitor enalapril possesses protection against testicular DNA damage and inflammation against STZinduced diabetic rat either due to their capability to scavenge ROS or to the inhibition of the conversion of angiotensin I to angiotensin II.…”

Section: Discussionmentioning

confidence: 99%

Enalapril reduces germ cell toxicity in streptozotocin-induced diabetic rat: investigation on possible mechanisms

Kushwaha

Jena

2011

Naunyn-Schmiedeberg's Arch Pharmacol

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Diabetes mellitus, a state of persistent hyperglycemia, is a major cause of micro- and macrovascular diseases. It affects nearly every system in the body including the reproductive system. Abnormalities in spermatogenesis and sexual function have been documented in animal models for both types of diabetes. The purpose of the present study is to determine the possible protective effects of enalapril against the germ cell toxicity in diabetic rat. Sprague-Dawley rats were divided into four groups: (1) control, (2) control + enalapril, (3) diabetic, and (4) diabetic + enalapril. Enalapril was administered per orally for 4 and 8 weeks continuously. After the treatment, animals were sacrificed and blood glucose level, sperm count, sperm DNA damage, apoptotic cell death, immunohistochemistry of 8-oxo- 7,8-dihydro- 2'-deoxyguanosine, and the cellular toxicity were performed. Furthermore, western blotting was performed to evaluate the expression of NFκB and COX-2 in testes. The results of the present study indicate that intervention of enalapril ameliorates the sperm DNA damage, reduces the oxidative stress, and down-regulates the expression of NFκB and COX-2 expression in streptozotocin-induced diabetic rat.

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Section: Discussionmentioning

confidence: 99%

Enalapril reduces germ cell toxicity in streptozotocin-induced diabetic rat: investigation on possible mechanisms

Kushwaha

Jena

2011

Naunyn-Schmiedeberg's Arch Pharmacol

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“…In support of a pathological role for oxidative stress within the nucleus, Schupp and colleagues find that ANG II-induced DNA damage in the perfused kidney, and LLC-PK proximal tubule cells was attenuated by either AT 1 receptor blockade or antioxidant treatment (83,84). Associated with the increase in DNA damage, ANG II also stimulated intracellular ROS (increased DCF fluorescence), although the ANG II concentration in the intact LLC-PK cells was 170-fold greater than that used in the isolated nuclei (83). In cardiomyocytes, ANG II also was more potent to stimulate the transcription factor NF-B when applied to isolated nuclei than to the intact cells (96).…”

Section: Nuclear Receptorsmentioning

confidence: 99%

Review:Novel roles of nuclear angiotensin receptors and signaling mechanisms

Gwathmey

Alzayadneh

Pendergrass

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

110

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The renin-angiotensin system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. The dysregulation of the RAS is considered a major influence in the development and progression of cardiovascular disease and other pathologies. Indeed, experimental and clinical evidence indicates that blockade of this system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT 1R) antagonists is an effective therapy to attenuate hypertension and diabetic renal injury, and to improve heart failure. Originally defined as a circulating system, multiple tissues express a complete RAS, and compelling evidence now favors an intracellular system involved in cell signaling and function. Within the kidney, intracellular expression of the three predominant ANG receptor subtypes is evident in the nuclear compartment. The ANG type 1 receptor (AT 1R) is coupled to the generation of reactive oxygen species (ROS) through the activation of phosphoinositol-3 kinase (PI3K) and PKC. In contrast, both ANG type 2 (AT 2R) and ANG-(1-7) (AT 7R) receptors stimulate nitric oxide (NO) formation, which may involve nuclear endothelial NO synthase (eNOS). Moreover, blockade of either ACE2-the enzyme that converts ANG II to ANG-(1-7)-or the AT 7 receptor exacerbates the ANG II-ROS response on renal nuclei. Finally, in a model of fetal programmed hypertension, the nuclear ROS response to ANG II is enhanced, while both AT 2 and AT7 stimulation of NO is attenuated, suggesting that an imbalance in the intracellular RAS may contribute to the development of programming events. We conclude that a functional intracellular or nuclear RAS may have important implications in the therapeutic approaches to cardiovascular disease. renin-angiotensin system; angiotensin converting enzyme; ACE2; neprilysin; kidney; nuclei; AT 1 ; AT 2 ; AT 7 , FROM THE EARLY STUDIES OF Tigerstedt and Bergman (101) that described renin activity in the kidney to the characterization of a pressor substance subsequently identified as ANG II by the laboratories of Braun-Menendez (6) (hypertensin) and Page (angiotonin) 50 years later (8), the characterization of the renin-angiotensin system (RAS) within the kidney and other tissues continues unabated to broaden our understanding of the functional aspects of this important hormonal system in blood pressure regulation and cardiovascular pathologies. Coupled with the discoveries of ANG I-converting enzyme (ACE) as the primary enzyme that forms ANG II in the circulation and tissue and the molecular identification of the ANG II type 1 receptor (AT 1 ) that confers the predominant actions of ANG II, the "classical" RAS was regarded as a sequential endocrine system to form ANG II for the maintenance of blood pressure through renal, vascular, and central mechanisms. There is, however, overwhelming evidence for a "nonclassical" RAS that results in the formation of novel peptide products with functional properties distinct from that of the ANG II-AT 1 receptor pathway (5,12,14,67,8...

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“…Oxidative products of lipids, proteins and DNA have been reported in humans and animals exposed to thinner fumes (Martínez-Alfaro et al, 2006;Ulakoglu et al, 1998). DNA oxidation has potentially genotoxic consequences; however, oxidative DNA damage can also be induced by a variety of nongenotoxic conditions or substances (Powers and Jackson 2008;Schmid et al, 2008). Studies of the genotoxic eff ects of thinner inhalation are few, and they have several limitations.…”

Section: Introductionmentioning

confidence: 99%

Thinner inhalation effects on oxidative stress and DNA repair in a rat model of abuse

Martínez-Alfaro

Cárabez-Trejo

Gallegos-Corona

et al. 2009

J of Applied Toxicology

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Humans can come into contact with thinner by occupational exposure or by intentional inhalation abuse. Numerous studies of workers for genotoxic effects of thinner exposure have yielded conflicting results, perhaps because co-exposure to variable other compounds cannot be avoided in workplace exposure studies. In contrast, there is no data concerning the genotoxic effects of intentional inhalation abuse. The aim of this project was to examine the genotoxic effects of thinner inhalation in an animal model of thinner abuse (rats exposed to 3000 ppm toluene, a high solvent concentration over a very short, 15 min time period, twice a day for 6 weeks). The data presented here provides evidence that thinner inhalation in our experimental conditions is able to induce weight loss, lung abnormalities and oxidative stress. This oxidative stress induces oxidative DNA damage that is not a characteristic feature of genotoxic damage. No significant difference in DNA damage and DNA repair (biomarkers of genotoxicity) in lymphocytes from thinner-treated and control rats was found. Lead treatment was used as a positive control in these assays. Finally, bone marrow was evaluated as a biomarker of cellular alteration associated with thinner inhalation. The observed absence of hemopoietic and genetic toxicity could be explained in part by the absence of benzene, the only carcinogenic component of thinner; however, benzene is no longer a common component of thinner. In conclusion, thinner did not cause genotoxic effects in an experimental model of intentional abuse despite the fact that thinner inhalation induces oxidative stress.

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Angiotensin II Induces DNA Damage in the Kidney

Cited by 48 publications

References 49 publications

Enalapril reduces germ cell toxicity in streptozotocin-induced diabetic rat: investigation on possible mechanisms

Enalapril reduces germ cell toxicity in streptozotocin-induced diabetic rat: investigation on possible mechanisms

Review:Novel roles of nuclear angiotensin receptors and signaling mechanisms

Thinner inhalation effects on oxidative stress and DNA repair in a rat model of abuse

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