Heme oxygenase attenuates angiotensin II-mediated superoxide production in cultured mouse thick ascending loop of Henle cells

Kelsen, Silvia; Patel, B. J.; Parker, Lawson B.; Vera, Trinity; Rimoldi, John M.; Gadepalli, Rama S; Drummond, Heather A.; Stec, David E.

doi:10.1152/ajprenal.00057.2008

Cited by 28 publications

(23 citation statements)

References 37 publications

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“…13 Induction of HO-1 in TALH cells results in the increased production of both bilirubin and CO, and both of which can attenuate Ang II-mediated superoxide production. 14 The attenuation of superoxide production in TALH tubules is significant, because several studies have shown that increases in superoxide can stimulate sodium reabsorption in the TALH both directly and by suppression of nitric oxide (NO) formation. [15][16][17] Another potential mechanism by which the antioxidant actions of HO-1 induction in TALH cells may lower blood pressure in Ang IIdependent hypertension is modification of the NO crosstalk between tubular and vascular structures to regulate blood flow in the renal medulla.…”

Section: Discussionmentioning

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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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: 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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“…We found that blocking sGC suppressed the inhibitory effect of CO on TGF, suggesting that CO inhibits TGF via the sGC/cGMP signaling pathway. On the other hand, CO was recently shown to decrease O 2 Ϫ in a mouse thick ascending limb cell line (15), and, if that were to occur in the MD, it would also indirectly block TGF by increasing NO availability. However, this is unlikely because our recent in vitro study showed that CO inhibition of TGF is independent of NO synthase blockade (29).…”

Section: Discussionmentioning

confidence: 99%

Heme oxygenase metabolites inhibit tubuloglomerular feedback in vivo

Wang

Garvin

D’Ambrosio

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Tubuloglomerular feedback (TGF) is a renal autoregulatory mechanism that constricts the afferent arteriole in response to increases in distal NaCl. Heme oxygenases (HO-1 and HO-2) release carbon monoxide (CO) and biliverdin, which may help control renal function. We showed in vitro that HO products inhibit TGF; however, we do not know whether this also occurs in vivo or the mechanism(s) involved. We hypothesized that in vivo HO-1 and HO-2 in the nephron inhibit TGF via release of CO and biliverdin. We first performed laser capture microdissection followed by real-time PCR and found that both HO-1 and HO-2 are expressed in the macula densa. We next performed micropuncture experiments in vivo on individual rat nephrons, adding different compounds to the perfusate, and found that an HO inhibitor, stannous mesoporphyrin (SnMP), potentiated TGF (P Ͻ 0.05, SnMP vs. control). The CO-releasing molecule (CORM)-3 partially inhibited TGF at 50 mol/l (P Ͻ 0.01, CORM-3 vs. control) and blocked it completely at higher doses. A soluble guanylyl cyclase (sGC) inhibitor, LY83583, blocked the inhibitory effect of CORM-3 on TGF. Biliverdin also partially inhibited TGF (P Ͻ 0.01, biliverdin vs. control), most likely attributable to decreased superoxide (O 2 Ϫ ) because biliverdin was rendered ineffective by tempol, a O 2 Ϫ dismutase mimetic. We concluded that HO-1 and HO-2 in the nephron inhibit TGF by releasing CO and biliverdin. The inhibitory effect of CO on TGF is mediated by the sGC/cGMP signaling pathway, whereas biliverdin probably acts by reducing O 2 Ϫ .stop-flow pressure; afferent arteriole; carbon monoxide; biliverdin AFFERENT ARTERIOLE (Af-Art) resistance determines renal blood flow and glomerular hydrostatic pressure and thus plays a central role in the development of hypertension and hypertensive nephropathy. Af-Art resistance is controlled by myogenic tone (19), vasoactive hormones (24), tubuloglomerular feedback (TGF) (35), and connecting tubule glomerular feedback (31). TGF is the mechanism by which the macula densa (MD) senses increases in luminal NaCl and signals the Af-Art to constrict (34). It is blocked by nitric oxide (NO) produced by the thick ascending loop of Henle and/or the MD (30,38). NO inhibits TGF by increasing cGMP in the MD, whereas superoxide (O 2 Ϫ ) potentiates TGF by scavenging NO (28). Heme oxygenases (HOs) are enzymes that catalyze conversion of heme to carbon monoxide (CO), biliverdin, and ferrous iron. Two active isoforms of HO, HO-1 and HO-2, have been described (2). The kidney constitutively expresses HO-2 mainly within epithelial cells of the thick ascending limb, distal convoluted and connecting tubules, and preglomerular arterioles (8, 12). HO-1 is normally low and contributes to HO activity only when it is induced as a result of some pathological condition (8). In vivo studies suggest that endogenous HO products can cause renal vasodilatation, diuresis, and natriuresis because metalloporphyrins (which inhibit HOs) increase blood pressure (14) and decrease renal blood flow (25, 42), gl...

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“…The exaggerated vasoconstrictive response when HO activity is inhibited may also reflect decreased kidney content of bilirubin. Bilirubin effectively scavenges superoxide anion generated by ANG II (17,30), and the generation of superoxide anion is incriminated in the vasoconstrictive and other actions of ANG II. However, oxidative stress, as reflected by whole kidney content of lipid peroxidation products and protein carbonyl content, was not increased by ANG II, either in the presence or absence of SnMP.…”

Section: Discussionmentioning

confidence: 99%

Heme oxygenase activity as a determinant of the renal hemodynamic response to low-dose ANG II

Nath

Hernandez

Croatt

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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II causes renal injury through hemodynamic and other effects, and pressor doses of ANG II induce heme oxygenase-1 (HO-1) as a protective response. The present studies examined the hemodynamic effects of more clinically relevant, lower doses of ANG II and the role of HO activity in influencing these effects. Under euvolemic conditions, ANG II increased arterial pressure and renal vascular resistance. ANG II did not induce oxidative stress, inflammation/injury-related gene expression, or proteinuria and did not alter extrarenal vascular reactivity. At these doses, ANG II failed to increase HO-1 or HO-2 mRNA expression or HO activity. Inhibiting HO activity in ANG II-treated rats by tin mesoporphyrin further increased renal vascular resistances, decreased renal blood flow, and blunted the rise in arterial pressure without inducing oxidative stress or altering expression of selected vasoactive/ injury/inflammation-related genes; tin mesoporphyrin did not alter vasorelaxation of mesenteric resistor vessels. We conclude that in this model renal vasoconstriction occurs without the recognized adverse effects of ANG II on glomerular filtration rate, renal blood flow, oxidative stress, vascular reactivity, proteinuria, and injury-related gene expression; renal HO activity is essential in preserving perfusion of the ANG II-exposed kidney. These findings represent an uncommon example wherein function of a stressed organ (by ANG II), but not that of the unstressed organ, requires intact renal HO activity, even when the imposed stress neither induces HO-1 nor HO activity. These findings may be germane to conditions attended by heightened ANG II levels, ineffective renal perfusion, and susceptibility to acute kidney injury. tin mesoporphyrin; ischemia ANG II IS A MAJOR CONTRIBUTOR to chronic kidney disease by virtue of its hemodynamic, proinflammatory, and profibrotic effects. Indeed, agents that interrupt the generation of ANG II and the engagement of ANG II with its receptor comprise a fundamental therapeutic approach in the management of patients with chronic kidney disease (12,20,22). Such therapies, however, reduce but do not abort the progression of chronic kidney disease, and thus complementary strategies that can synergize with these therapies would be of interest. In this regard, a fundamental basis for the injurious effects of ANG II involves the imposition of oxidant stress via NADPH oxidase (35). Studies by us and others have demonstrated that ANG II induces the antioxidant gene heme oxygenase-1 (HO-1) (3, 4, 11) in the kidney in vivo and in vitro and that such induction of HO-1, by virtue of its antioxidant, anti-inflammatory, and vasorelaxant properties (1,2,15,24), is implicated as an adaptive, protective mechanism that can reduce the severity of ANG II-induced renal injury.An established approach employed in studying the pathogenetic basis for ANG II-induced renal injury utilizes the chronic administration of ANG II by osmotic minipumps. Such studies demonstrate that ANG II, so administered, provokes markedly i...

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Heme oxygenase attenuates angiotensin II-mediated superoxide production in cultured mouse thick ascending loop of Henle cells

Cited by 28 publications

References 37 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

Heme oxygenase metabolites inhibit tubuloglomerular feedback in vivo

Heme oxygenase activity as a determinant of the renal hemodynamic response to low-dose ANG II

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