Role of Renal Medullary Heme Oxygenase in the Regulation of Pressure Natriuresis and Arterial Blood Pressure

Li, Ningjun; Yi, Fan; Santos, Elisabete Alcantara dos; Donley, Dustin K.; Li, Pin‐Lan

doi:10.1161/01.hyp.0000250086.06137.fb

Cited by 59 publications

(78 citation statements)

References 49 publications

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“…The effect of TALH-specific induction of HO-1 on sodium transport in the TALH is supported by the observation that renal medullary inhibition of HO-1 was associated with increases in sodium and water reabsorption and development of salt-sensitive hypertension. 3 In contrast, previous studies have shown that the HO metabolite, carbon monoxide, enhanced sodium chloride reabsorption in isolated TALH tubules by stimulation of the apical 70-pS K+ channel. 12 One potential mechanism by which induction of HO-1 in TALH can decrease sodium transport is through antioxidant actions.…”

Section: Discussionmentioning

confidence: 86%

See 1 more Smart Citation

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: 86%

“…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 These data suggest an important role for HO and its metabolites in the regulation of both renal function and blood pressure.…”

mentioning

confidence: 90%

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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“…[22][23][24][25] Carbon monoxide also dilates blood vessels by directly activating potassium channels in vascular smooth muscle cells (SMCs). Stanford et al reported that CO can inhibit 2.…”

Section: Vasodilationmentioning

confidence: 99%

Application of carbon monoxide for treatment of acute kidney injury

Nakao

Yamada

Kohama

et al. 2014

Acute Medicine & Surgery

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Acute kidney injury in critically ill patients is common and associated with a substantial increase in morbidity and mortality. Even with aggressive medical care and renal replacement therapy, acute kidney injury remains a significant health care concern. Recent published reports offer new strategies for the prevention and amelioration of acute kidney injury using carbon monoxide. Although considered a toxic environmental gas, carbon monoxide has recently aroused scientific and clinical interest, as its beneficial effects and mechanisms of action have been substantially defined in various in vitro and in vivo experiments. The exogenous application of carbon monoxide can confer cytoprotection by modulating intracellular signaling pathways through its anti‐inflammatory, anti‐apoptotic, vasodilative, antithrombotic and antiproliferative properties. Thus, evidence is accumulating to support the notion of carbon monoxide treatment for acute kidney disease. In this review, we focus on the extensively analyzed advantageous value of treatment with inhaled/soluble carbon monoxide in the context of kidney injury. Mechanisms such as signaling pathways, as well as an expanded view regarding toxicity and side‐effects, are described broadly. In addition, we discuss the clinical applicability of carbon monoxide as a promising therapeutic strategy for the treatment of patients with acute kidney disease based on translating basic experimental findings into clinical application.

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“…82 However, results from whole-animal studies in which the levels of HO are altered have not supported an antinaturetic function of CO in the kidney. Recent studies by Li et al 83 have documented an increase in CO production in the renal medulla in response to increases in renal perfusion pressure. Because increases in Figure 2.…”

Section: Co and The Kidney: Beyond The Vasculaturementioning

confidence: 99%

“…85 Lastly, chronic inhibition of HO in the renal medulla attenuates pressure-natriuresis and hypertension in response to increases in sodium intake. 83 Whether salt-sensitive hypertension resulting from inhibition of HO in the medulla is the result of changes in medullary blood flow or alterations in tubular function is not known and warrants further investigation. CO signaling in renal tubular epithelial cells has not been extensively studied; however, because it uses similar signaling pathways as NO in the vasculature, is it possible that CO is able to activate similar pathways as NO in tubular epithelial cells.…”

Section: Co and The Kidney: Beyond The Vasculaturementioning

confidence: 99%

Role of Carbon Monoxide in Blood Pressure Regulation

2008

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C arbon monoxide (CO) is an odorless, colorless, tasteless gas that is generated in the environment as the result of combustion from stoves and engines among other sources. Approximately 500 people per year in the United States are victims of nonfire-associated CO poisoning according to the Centers for Disease Control and Prevention. CO poisoning is often fatal because of its interaction with hemoglobin, which renders it incapable of carrying oxygen-causing organs to become severely hypoxic. CO inhalation is believed to be fatally toxic at concentrations as little as 800 parts per million (ppm) or 0.08% in the air. Despite the lethal nature of this gas, several recent studies suggest that CO inhalation at low doses (Յ250 ppm), as well as increases in CO levels using CO releasing molecules (CORMs), offers protection against ischemic injury in the heart, liver, and kidney. [1][2][3][4] CO is endogenously produced in the body as a result of the metabolism of heme by heme oxygenase (HO), as well as from lipid peroxidation. 5,6 The catabolism of heme by HO also produces an equimolar amount of biliverdin, which is rapidly converted in the cell to bilirubin by the enzyme biliverdin reductase. 7 There are 2 major isoforms of HO responsible for CO production. HO-1 is expressed at very low levels under normal conditions but is highly induced by several stimuli, including heavy metals, ultraviolet light, endotoxin, shear stress, hypoxia, and oxidants. 8 HO-2 is the constitutively expressed form of the enzyme with the highest levels observed in the brain and testes. 9 Experimental evidence has demonstrated that systemic induction of HO has several beneficial actions on the cardiovascular system, including lowering of blood pressure, protection against myocardial infarction, and prevention of atherosclerosis. 10 -12 Although the cardiovascular actions of HO induction have been established, the role of CO in mediating these responses is not clear. The purpose of this review is to outline the potential antihypertensive actions of CO and highlight areas that may pose new opportunities for the development of novel therapeutic targets for the treatment of hypertension. Altering CO Levels In Vivo: Tools of the TradeThere are 3 main approaches that have been used to alter tissue levels of CO in vivo, which need to be briefly discussed. These include inhibition/induction of HO, CO inhalation, and CORMs. Each of these approaches has its own advantages and limitations depending on the specific experimental settings in which tissue levels of CO are to be altered. HO induction/inhibition has been widely used because of the fact that most of the endogenous CO produced in vivo is derived from HO. Given the routine ability to alter HO in a tissue-and temporal-specific fashion either pharmacologically or genetically, this is an attractive option for examining CO in vivo. However, there are several limitations in altering HO levels to examine the role of CO in vivo. First among these is the specificity of the majority of the metalloporphyr...

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Role of Renal Medullary Heme Oxygenase in the Regulation of Pressure Natriuresis and Arterial Blood Pressure

Cited by 59 publications

References 49 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

Application of carbon monoxide for treatment of acute kidney injury

Role of Carbon Monoxide in Blood Pressure Regulation

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