Increase in heme oxygenase-1 levels ameliorates renovascular hypertension

Botros, Fady T.; Schwartzman, Michal Laniado; Stier, Charles T.; Goodman, Alvin I.; Abraham, Nader G.

doi:10.1111/j.1523-1755.2005.00745.x

Cited by 103 publications

(94 citation statements)

References 64 publications

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“…[4][5][6][7][8][9] Despite these results, the mechanism by which systemic induction of HO-1 lowers blood pressure is not known. We have previously shown that kidney-specific induction of HO-1 through renal medullary interstitial infusion of cobalt protoporphyrin attenuates the development of Ang II-dependent hypertension.…”

Section: Discussionmentioning

confidence: 91%

“…[4][5][6][7][8][9] Recently, we reported that kidney-specific induction of HO-1 by renal medullary interstitial infusion of cobalt protoporphyrin attenuated the development of angiotension II (Ang II) -dependent hypertension. 10 Although that work was the first to report that renal-specific induction of HO-1 could attenuate Ang II-dependent hypertension, the importance of vascular versus tubular induction of HO-1 could not be distinguished in this model.…”

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confidence: 99%

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Expression of Heme Oxygenase-1 in Thick Ascending Loop of Henle Attenuates Angiotensin II-Dependent Hypertension

Stec

Drummond

Gousette

et al. 2012

Journal of the American Society of Nephrology

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Kidney-specific induction of heme oxygenase-1 (HO-1) attenuates the development of angiotensin II (Ang II) -dependent hypertension, but the relative contribution of vascular versus tubular induction of HO-1 is unknown. To determine the specific contribution of thick ascending loop of Henle (TALH) -derived HO-1, we generated a transgenic mouse in which the uromodulin promoter controlled expression of human HO-1. Quantitative RT-PCR and confocal microscopy confirmed successful localization of the HO-1 transgene to TALH tubule segments. Medullary HO activity, but not cortical HO activity, was significantly higher in transgenic mice than control mice. Enhanced TALH HO-1 attenuated the hypertension induced by Ang II delivered by an osmotic minipump for 10 days (13963 versus 15362 mmHg in the transgenic and control mice, respectively; P,0.05). The lower blood pressure in transgenic mice associated with a 60% decrease in medullary NKCC2 transporter expression determined by Western blot. Transgenic mice also exhibited a 36% decrease in ouabain-sensitive sodium reabsorption and a significantly attenuated response to furosemide in isolated TALH segments,. In summary, these results show that increased levels of HO-1 in the TALH can lower blood pressure by a mechanism that may include alterations in NKCC2-dependent sodium reabsorption. Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme to biliverdin, during which both carbon monoxide (CO) gas and free iron are released. Biliverdin is then reduced to bilirubin by the ubiquitous enzyme biliverdin reductase. There are two major isoforms of HO that are responsible for the breakdown of heme, HO-1 and HO-2. HO-2 is the constitutively expressed isoform, whereas HO-1 is inducible by a wide variety of stimuli, including hypoxia, metals, ischemia, and oxidative stress. In the kidney, both isoforms of HO are present, with the highest level of expression of both isoforms in the renal medulla under basal conditions. 1,2 HO enzymes are not only expressed in the renal medulla, but their metabolites, CO and bilirubin, play an important role in the regulation of both renal vascular and tubular function. Renal medullary infusion of the general HO inhibitor, zinc deuteroporphyrin 2,4-bis glycol, results in a significant decrease in renal medullary blood flow. 1 In the renal tubules, increases in perfusion pressure increase CO levels, and inhibition of HO activity results in significant attenuation of pressure natriuresis and development of salt-sensitive hypertension. 3

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

Expression of Heme Oxygenase-1 in Thick Ascending Loop of Henle Attenuates Angiotensin II-Dependent Hypertension

Stec

Drummond

Gousette

et al. 2012

Journal of the American Society of Nephrology

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“…Therefore, these results would be more consistent with what's observed in hypertensive patients. Previous studies have observed no change in blood pressure during insulin pretreatment (Johansson et al 2008) and a decrease in blood pressure during heme induction (Botros et al 2005). Differences in previous studies could be attributed to the class, dose and/or type of administered agent in the study.…”

Section: Discussionmentioning

confidence: 99%

Regulation of heme oxygenase-1 induction during recurrent insulin induced hypoglycemia

Quadri¹,

Prathipati²,

Jackson³

et al. 2014

IJM

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Background: Recurrent insulin induced hypoglycemia (RIIH) is an unavoidable risk of conventional therapeutic management of insulin dependent diabetes mellitus and is a primary cause of impaired glucose counter regulation. Circulating angiotensin II (AngII) has been reported to be elevated in diabetic models, and is linked to the promotion of hypertension. Objective: The current study was performed to evaluate the hypothesis that chronic insulin injections and/or hypoglycemia promotes hypertension via an increase in AngII, which increases endogenous carbon monoxide (CO) through an induction in heme oxygenase (HO-1). Methods: Male Sprague Dawley rats (200 250g) were treated for 2 weeks with daily injections of 7U/kg insulin or diluent. On the 14th day, surgery was performed and rats were administered various doses of captopril (2mg/kg, 8mg/kg, and 12mg/kg) or vehicle. Following the dose evaluation, subsets of previously treated animals were treated with vehicle, DALA (80g/kg), Captopril (12mg/kg) or a combination of DALA (80g/kg) + CAP (12mg/kg). Results: A dose dependent decrease in blood pressure was observed during captopril treatment in RIIH hypertensive rats. However, there was no change in urine output among the treatment groups. Captopril and DALA+CAP treatments produced a reduction in blood pressure as compared to animals treated with DALA alone. Carboxyhemoglobin and AngII concentrations were also reduced in animals treated with captopril and DALA+CAP. In addition, HO-1 protein levels in heart and kidney were reduced when compared to DALA treated animals. Conclusion: These results demonstrate that RIIH promotes an increase in circulating AngII and hypertension via an induction in HO-1, which significantly increases endogenous CO levels. Keywords: Angiotensin II, Carbon Monoxide, Heme Oxygenase, Recurring Insulin-Induced Hypoglycemia (RIIH).

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“…Prior studies have demonstrated that hyperexpression of HO-1 by genetic or pharmacologic approaches may result in a relatively weak increase in cell HO activity, suggesting that much of the expressed protein is nonfunctional Quan et al, 2004;Teng et al, 2004;Botros et al, 2005). Quantification of activity may therefore be a more accurate index of the therapeutic potential of a drug or construct in a particular cell population than measurement of protein expression per se.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte-specific heme oxygenase-1 hyperexpression attenuates heme-mediated oxidative injury

Benvenisti-Zarom

Regan

2007

Neurobiology of Disease

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In prior studies, we have observed that HO activity protects astrocytes from heme-mediated injury, but paradoxically increases neuronal injury. In this study, we tested the hypothesis that an adenovirus encoding the human HO-1 gene driven by an enhanced glial fibrillary acidic protein promoter (Ad-GFAP-HO-1) would increase HO-1 expression selectively in astrocytes, and provide cytoprotection. Treatment with 100 MOI Ad-GFAP-HO-1 for 24h resulted in HO-1 expression that was 6.4-fold higher in cultured primary astrocytes than in neurons. Astrocyte HO activity was increased by approximately fourfold over baseline, which was sufficient to reduce cell death after 24 h hemin exposure by 60%, as assessed by both MTT and LDH release assays. A similar reduction in cell protein oxidation, quantified by carbonyl assay, was also observed. These results suggest that HO-1 transgene expression regulated by an enhanced GFAP promoter selectively increases HO-1 expression in astrocytes, and is cytoprotective. Further investigation of this strategy in vivo is warranted.

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Increase in heme oxygenase-1 levels ameliorates renovascular hypertension

Cited by 103 publications

References 64 publications

Expression of Heme Oxygenase-1 in Thick Ascending Loop of Henle Attenuates Angiotensin II-Dependent Hypertension

Expression of Heme Oxygenase-1 in Thick Ascending Loop of Henle Attenuates Angiotensin II-Dependent Hypertension

Regulation of heme oxygenase-1 induction during recurrent insulin induced hypoglycemia

Astrocyte-specific heme oxygenase-1 hyperexpression attenuates heme-mediated oxidative injury

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