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            Receptor Blockade Improves Vasorelaxation in Experimental Renal Failure

Kööbi, Peeter; Kalliovalkama, Jarkko; Jolma, Pasi; Rysä, Jaana; Ruskoaho, Heikki; Vuolteenaho, Olli; Kähönen, Mika; Tikkanen, Ilkka; Fan, Meng; Ylitalo, Pauli; Pörsti, Ilkka

doi:10.1161/01.hyp.0000073782.30879.16

Cited by 32 publications

(52 citation statements)

References 39 publications

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“…We suspect that NF-B activation is involved in mediating the increase of ICAM-1 expression in the nonlesioned intima because the above-mentioned stimuli are all characteristically in excess in uremia. Uremic patients often have elevated plasma or tissue concentrations of proinflammatory cytokines (IL-6, TNF␣, and IL-1) (35,36), advanced glycation end products (37), and of angiotensin II (38), and they frequently display evidence of increased oxidative stress (39,40). NF-B also controls VCAM-1 expression (41).…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

Bro¹,

Moeller²,

Andersen

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Chronic renal failure markedly accelerates atherosclerosis in apolipoprotein-E-deficient mice, but the mechanism is unknown. The recruitment of inflammatory cells in the arterial wall by vascular adhesion molecules plays a key role in the formation of classical atherosclerosis. This study examines whether the expression of vascular adhesion molecules is increased in uremic atherosclerosis. Uremia was induced by 5/6 nephrectomy; control mice were sham-operated. After 2 wk of uremia, no lesion formation could be demonstrated in uremic or control mice. After 12 wk, aortas from uremic mice had a 9.8-fold increase of the aortic plaque area fraction compared with control mice (P Ͻ 0.0001). The aortic expression of intercellular adhesion molecule-1 (ICAM-1) mRNA in uremic mice was 215 Ϯ 31% (P Ͻ 0.05) and 243 Ϯ 55% (P Ͻ 0.05) of that in controls after 2 and 12 wk, respectively (n ϭ 9 ϫ 4). In contrast, aortic expression of vascular cell adhesion molecule-1 (VCAM-1) mRNA in uremic mice was unchanged after 2 wk but increased to 237 Ϯ 40% (P Ͻ 0.01) of that in control mice after 12 wk. On immunohistochemistry of aortas from uremic mice, ICAM-1 was predominantly present in endothelial cells both in nonlesioned and lesioned aortas, whereas VCAM-1 was predominantly present in the medial smooth muscle cell layer in lesioned aortas. The plasma concentration of soluble ICAM-1 (sICAM-1) (but not of sVCAM-1) was slightly elevated after 2 wk of uremia. In contrast, both sICAM-1 and sVCAM-1 plasma concentrations were markedly higher in uremic than control mice after 12 wk. These results suggest that uremic atherosclerosis is preceded by an upregulation of ICAM-1 expression in arterial endothelium and that formation of early uremic lesions is accompanied by upregulation of VCAM-1 expression in the medial smooth muscle cell layer.

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Section: Discussionmentioning

confidence: 99%

Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

Bro¹,

Moeller²,

Andersen

et al. 2004

Journal of the American Society of Nephrology

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“…The systolic blood pressures and body weights in all groups were comparable at the beginning and end of the study (background data has been published previously [see 12]). The final systolic blood pressures were 151 ± 5, 138 ± 7, 148 ± 5 and 152 ± 6 mm Hg in the Sham, Losartan-Sham, NX and Losartan-NX groups, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Male Sprague-Dawley rats were subjected to 5/6 nephrectomy or sham operation at the age of 8 weeks [for detailed information, see 12]. The systolic blood pressures were measured using the tail-cuff method.…”

Section: Methodsmentioning

confidence: 99%

“…Four weeks after the operations, the rats were divided into untreated (Sham, n = 9 and NX, n = 10) and losartan (20 mg/kg/day orally)-treated groups (Losartan-Sham, n = 8 and Losartan-NX, n = 8) of equal mean systolic blood pressures and body weights. The rats were sacrificed at the age of 20 weeks, and blood and tissue samples were taken as previously described [12]. The experimental design of the study was approved by the Animal Experimentation Committee of the University of Tampere, Finland, and the Provincial Government of Western Finland Department of Social Affairs and Health, Finland.…”

Section: Methodsmentioning

confidence: 99%

“…In hypertension the impaired endothelium-mediated relaxation can be ameliorated by treatment with AT 1 receptor blockers [7, 11]. Recently we found that losartan therapy could normalize the impaired resistance artery relaxation in uremic rats [12]. Since large arteries are the main target of vascular complications in CRF, in this study we examined the influence of chronic AT 1 receptor blockade on the tone of the main branch of the mesenteric artery, and tested the hypothesis that losartan treatment will correct the impairments in the regulation of conduit-size artery tone in rats subjected to subtotal nephrectomy.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Angiotensin II Type 1 Receptor Blockade on Conduit Artery Tone in Subtotally Nephrectomized Rats

Kööbi

Jolma²,

Kalliovalkama³

et al. 2004

Nephron Physiol

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Background: Angiotensin II type 1 (AT₁) receptor antagonists provide end-organ protection and enhance resistance artery relaxation in uremia. The effect of AT₁ blockade on conduit artery function in renal failure is unknown. Methods: The influence of 8-week losartan therapy (20 mg/kg/day) on tone of isolated main branch mesenteric arterial rings was studied in 5/6 nephrectomized (NX) rats. Blood and urine chemistry were examined, and AT₁ receptors quantified using autoradiography. Results: NX rats showed decreased creatinine clearance without change in blood pressure. Losartan did not influence these variables, although [¹²⁵I]-Sar1,Ile8-angiotensin II binding to renal AT₁ receptors was significantly prevented. Vasoconstriction to endothelin-1 was reduced by losartan in NX and Sham rats. Vasorelaxation to acetylcholine was attenuated in untreated but not in losartan-treated NX rats, and experiments with Ca²⁺-activated K⁺ channel blockers suggested that impaired endothelium-mediated response after NX was due to deficient relaxation via K⁺ channels. Endothelium-independent relaxation to levcromakalim, adenosine triphosphate-sensitive K⁺ channel agonist, was impaired in untreated but not in losartan-treated NX rats. Conclusion: Losartan reduced conduit artery vasoconstriction to endothelin-1 and augmented vasorelaxation via K⁺ channels in NX rats, although blood pressure and renal function were unchanged. Therefore, AT₁ blockade confers functional benefits to large arteries in renal failure.

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Knockdown of periostin attenuates 5/6 nephrectomy‐induced intrarenal renin–angiotensin system activation, fibrosis, and inflammation in rats

Bian

Bai

et al. 2019

Journal Cellular Physiology

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To simulate clinical features in human chronic kidney disease (CKD), SD rats were subjected to 5/6 nephrectomy in this study. We found that periostin gene was upregulated in the remnant kidneys using Agilent gene microarrays, and further explored its role via in vivo and in vitro experiments. Intrarenal renin-angiotensin system (RAS) was activated in 5/6 nephrectomized rats and partly deactivated by injection of adenoviruses encoding short hairpin RNA against periostin (sh-periostin).Renal fibrosis in nephrectomized rats and profibrotic transforming growth factor-β-induced epithelial-mesenchymal transition (EMT) and ERK1/2 activation in NRK-52E cells were suppressed by sh-periostin. Moreover, knockdown of periostin decreased the generation of Interleukin 6 (IL6) and tumor necrosis factor-α (TNF-α) and accelerated p62 degradation in the remnant kidneys. Both HK-2 cells treated with recombinant periostin and NRK-52E cells infected with adenoviruses expressing periostin produced more IL6 and TNF-α than control cells and displayed impaired autophagy as evidenced by inhibition of LC3II to LC3I conversion, Beclin 1 expression, and p62 degradation. By treating cells with rapamycin, an inhibitor of mamalian target of rapamycin known to activate autophagy, we noted that periostininduced inflammation was inhibited. Additionally, HK-2 cells transfected with periostin overexpression plasmid generated more CCL2 and CXCL10, two important chemotactic factors, than untransfected cells. Conditioned medium from HK-2 cells overexpressing periostin augmented chemotaxis of THP-1 macrophages. Collectively, our work demonstrates that knockdown of periostin attenuates 5/6 nephrectomyinduced intrarenal RAS activation, fibrosis, and inflammation in rats. These findings advance our understanding of periostin's role in CKD induced by nephron loss. K E Y W O R D S autophagy, chronic kidney failure, EMT, inflammation, periostin, RAS

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AT ₁ Receptor Blockade Improves Vasorelaxation in Experimental Renal Failure

Cited by 32 publications

References 39 publications

Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

Effect of Angiotensin II Type 1 Receptor Blockade on Conduit Artery Tone in Subtotally Nephrectomized Rats

Knockdown of periostin attenuates 5/6 nephrectomy‐induced intrarenal renin–angiotensin system activation, fibrosis, and inflammation in rats

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AT 1 Receptor Blockade Improves Vasorelaxation in Experimental Renal Failure

Cited by 32 publications

References 39 publications

Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

Effect of Angiotensin II Type 1 Receptor Blockade on Conduit Artery Tone in Subtotally Nephrectomized Rats

Knockdown of periostin attenuates 5/6 nephrectomy‐induced intrarenal renin–angiotensin system activation, fibrosis, and inflammation in rats

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Product

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AT ₁ Receptor Blockade Improves Vasorelaxation in Experimental Renal Failure