Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension

Quaschning, Thomas; Voß, Florian; Relle, Katharina; Kalk, Philipp; Vignon-Zellweger, Nicolas; Pfab, Thiemo; Bauer, Christian; Theilig, Franziska; Bachmann, S.; Kraemer-Guth, Annette; Wanner, Christoph; Theuring, Franz; Galle, Jan; Hocher, Berthold

doi:10.1681/asn.2006050541

Cited by 58 publications

(36 citation statements)

References 51 publications

(48 reference statements)

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“…We furthermore showed in ET+/+ eNOS-/-crossbred mice that the absence of eNOS promotes hypertension in states of ET-1 upregulation [26] . On the other hand, inhibition of iNOS is known to attenuate impairment of organ function in states of elevated ET-1 levels [27] .…”

Section: Introductionmentioning

confidence: 77%

“…Blood pressure was measured by the tail-cuff method (Blood Pressure Monitor BMN-1756, Föhr Medical Instruments, Seeheim, Germany) in unanesthetized mice that underwent 4 days of extensive training to get used to this procedure [26] . For every datapoint, five measurements were performed and mean values of five subsequent measurements were calculated.…”

Section: Blood Pressurementioning

confidence: 99%

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Lack of iNOS Impairs Endothelial Function in Endothelin-1 Transgenic Mice

Quaschning

Voß²,

Herzfeld³

et al. 2008

Kidney Blood Press Res

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Background: Endothelin-1 (ET-1) is one of the most potent biologic vasoconstrictors. Nevertheless, transgenic mice overexpressing ET-1 exhibit normal blood pressure. We hypothesized that in states of ET-1 overproduction, the lack of counterregulatory mediators such as nitric oxide (NO), produced by the inducible NO synthase (iNOS), may critically impair endothelial function and may result in blood pressure elevation. Methods: We generated crossbred animals of ET transgenic mice (ET+/+) and iNOS knockout mice (iNOS–/–) and evaluated blood pressure and endothelial function in these animals. Endothelium-dependent and -independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings to acetylcholine, sodium nitroprusside, and ET-1, alone or in the presence of BQ123 or BQ788. Results: Systolic blood pressure was similar in ET+/+, iNOS–/– and wild-type mice, but was significantly elevated in ET+/+ iNOS–/– crossbred animals versus ET+/+ mice. Maximum endothelium-dependent relaxation was enhanced in ET+/+ mice (95 ± 5 vs. 78 ± 5% of preconstriction in wild-type littermates; p < 0.05). Additional knockout of iNOS led to a significant decrease of endothelium-dependent relaxation in combined ET+/+ iNOS–/– animals (75 ± 6%; p < 0.05 vs. ET+/+ mice). Endothelium-independent relaxation was comparable among all groups. Maximum vascular contraction to ET-1 was reduced in ET+/+ mice (33 ± 4%), iNOS–/– mice (38 ± 5%) and ET+/+ iNOS–/– mice (44 ± 4%) to a similar extent as compared with wild-type littermates (66 ± 4%; p < 0.05). Conclusions: Our data show for the first time that in transgenic mice overexpressing human ET-1, additional knockout of iNOS results in impaired endothelium-dependent vasodilatation thus contributing to elevated blood pressure in ET+/+ iNOS–/– animals.

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Section: Introductionmentioning

confidence: 77%

Section: Blood Pressurementioning

confidence: 99%

Lack of iNOS Impairs Endothelial Function in Endothelin-1 Transgenic Mice

Quaschning

Voß²,

Herzfeld³

et al. 2008

Kidney Blood Press Res

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“…Proteins of murine kidney were extracted as previously described [34], additionally supplemented with inhibitor of phosphatases (PhosStop, Roche diagnostics, Indianapolis, IN). Proteins were electrophoretically separated and transferred to a nitrocellulose membrane using semi-dry equipment.…”

Section: Methodsmentioning

confidence: 99%

Relaxin-2 Does Not Ameliorate Nephropathy in an Experimental Model of Type-1 Diabetes

Dschietzig

Krause-Relle

Hennequin

et al. 2015

Kidney Blood Press Res

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Background/Aims: In diabetic nephropathy (DN), the current angiotensin-II-blocking pharmacotherapy is frequently failing. For diabetic cardiomyopathy (DC), there is no specific remedy available. Relaxin-2 (Rlx) - an anti-fibrotic, anti-inflammatory, and vasoprotecting peptide - is a candidate drug for both. Methods: Low-dose (32 µg/kg/day) and high-dose (320 µg/kg/day) Rlx were tested against vehicle (n = 20 each) and non-diabetic controls (n = 14) for 12 weeks in a model of type-1 diabetes induced in endothelial nitric oxide synthase knock-out (eNOS-KO) mice by intraperitoneal injection of streptozotocin. Results: Diabetic animals showed normal plasma creatinine, markedly increased albuminuria and urinary malonyldialdehyde, elevated relative kidney weight, glomerulosclerosis, and increased glomerular size, but no relevant interstitial fibrosis. Neither dose of Rlx affected these changes although the drug was active and targeted plasma levels were achieved. Of note, we found no activation of the renal TGF-β pathway in this model. In the hearts of diabetic animals, no fibrotic alterations indicative of DC could be determined which precluded testing of the initial hypothesis. Conclusions: We investigated a model showing early DN without overt tubulo-interstitial fibrosis and activation of the TGF-β-Smad-2/3 pathway. In this model, Rlx proved ineffective; however, the same may not apply to other models and types of diabetes.

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“…[17][18][19] Because NO inhibits ET-1 expression, 20,21 this suggests that decreased eNOS/NO might exacerbate pre-eclampsia by upregulating ET-1. To test this, we first determined the level of preproET-1 mRNA expression in the kidneys, which did not differ in mice with Ad Fc virus ( Figure 4A).…”

Section: Upregulation Of Preproet-1 and Et A Receptor In Enosmentioning

confidence: 99%

eNOS Deficiency Acts through Endothelin to Aggravate sFlt-1–Induced Pre-Eclampsia–Like Phenotype

Hagaman

Kim

et al. 2012

Journal of the American Society of Nephrology

109

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Excess soluble fms-like tyrosine kinase 1 (sFlt-1) of vascular endothelial growth factor receptor 1 secreted from the placenta causes pre-eclampsia-like features by antagonizing vascular endothelial growth factor signaling, which can lead to reduced endothelial nitric oxide synthase (eNOS) activity; the effect of this concomitant decrease in eNOS activity is unknown. We tested whether the decrease in nitric oxide occurring in female mice lacking eNOS aggravates the pre-eclampsia-like phenotype induced by increased sFlt-1. Untreated eNOS-deficient female mice had higher BP than wild-type mice. Adenovirus-mediated overexpression of sFlt-1 increased systolic BP by approximately 27 mmHg and led to severe loss of fenestration of glomerular capillary endothelial cells in both eNOS-deficient and wild-type mice. However, only the eNOS-deficient sFlt-1 mice exhibited severe foot process effacement. Compared with wild-type sFlt-1 mice, eNOS-deficient sFlt-1 mice also showed markedly higher urinary albumin excretion (467674 versus 174623 mg/d), lower creatinine clearance (126629 versus 452663 ml/min), and more severe endotheliosis. Expression of preproendothelin-1 (ET-1) and its ET A receptor in the kidney was higher in eNOS-deficient sFlt-1 mice than in wild-type sFlt-1 mice. Furthermore, the selective ET A receptor antagonist ambrisentan attenuated the increases in BP and urinary albumin excretion and ameliorated endotheliosis in both wild-type and eNOS-deficient sFlt-1 mice. Ambrisentan improved creatinine clearance and podocyte effacement in eNOS-deficient sFlt-1 mice. In conclusion, reduced maternal eNOS/nitric oxide exacerbates the sFlt1-related pre-eclampsia-like phenotype through activation of the endothelin system. Pre-eclampsia is a pregnancy-related disease characterized by high BP and proteinuria, and affects 3%-5% of all pregnancies. 1,2 Although the etiology of pre-eclampsia is not fully understood, it is widely accepted that placental hypoxia/ischemia increases the production by the placenta of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin, and likely other factors. 1 Increased sFlt-1 is recognized as one of the most important causal factors for maternal symptoms of pre-eclampsia. 1 sFlt-1 is a splice variant of vascular endothelial growth factor (VEGF) receptor-1 that lacks the cytoplasmic and transmembrane domains, but retains the ligandbinding domain. sFlt-1 decreases the chance of VEGF binding to its signaling receptor, and reduces the phosphorylation of Ser 1177 of endothelial nitric oxide synthase (eNOS) by VEGF and the activity of eNOS. 3 Plasma concentration of sFlt-1 is

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Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension

Cited by 58 publications

References 51 publications

Lack of iNOS Impairs Endothelial Function in Endothelin-1 Transgenic Mice

Lack of iNOS Impairs Endothelial Function in Endothelin-1 Transgenic Mice

Relaxin-2 Does Not Ameliorate Nephropathy in an Experimental Model of Type-1 Diabetes

eNOS Deficiency Acts through Endothelin to Aggravate sFlt-1–Induced Pre-Eclampsia–Like Phenotype

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