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  • 1
    In: American Journal of Nephrology, S. Karger AG, Vol. 39, No. 5 ( 2014), p. 400-408
    Abstract: 〈 b 〉 〈 i 〉 Background: 〈 /i 〉 〈 /b 〉 Disturbed calcium-phosphorus metabolism is associated with increased kidney angiotensin-converting enzyme (ACE) in experimental chronic renal insufficiency (CRI). However, information about the effects of phosphate binding and loading on vascular ACE is lacking. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 Fifteen weeks after 5/6 nephrectomy 〈 b 〉 〈 /b 〉 (NX), rats were placed on a phosphate-binding (NX+Ca, 3.0% Ca), phosphate-loading (NX+Pi, 1.5% Pi), or control diet for 12 weeks (NX and sham). 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 Aortic ACE, blood pressure, plasma phosphate, and parathyroid hormone were increased in the NX and NX+Pi groups, but were reduced with phosphate binding. Endothelium-mediated relaxations of isolated mesenteric conduit artery rings to acetylcholine were impaired in the NX and NX+Pi groups, but did not differ from sham in NX+Ca rats. Experiments with nitric oxide (NO) synthase inhibition in vitro suggested that the NO-mediated component of acetylcholine response was lower in the NX and NX+Pi groups, but did not differ from sham in NX+Ca rats. In all NX groups, aortic endothelial NO synthase (eNOS) was reduced, while plasma and urine concentrations of NO metabolites were increased. Aortic nitrated proteins and calcification were increased in the NX and NX+Pi groups when compared with the NX+Ca and sham groups. 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 Hypertension in the NX model of CRI was associated with reduced vasorelaxation, decreased eNOS, and increased ACE and nitrated proteins in the aorta. Phosphate binding with calcium carbonate enhanced vasorelaxation via endogenous NO and suppressed elevation of ACE and nitrated proteins, suggesting reduced vascular oxidative stress. Our findings support the view that correction of the calcium-phosphorus balance prevents CRI-induced vascular pathophysiology.
    Type of Medium: Online Resource
    ISSN: 0250-8095 , 1421-9670
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2014
    detail.hit.zdb_id: 1468523-1
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  • 2
    In: American Journal of Nephrology, S. Karger AG, Vol. 35, No. 5 ( 2012), p. 401-408
    Abstract: 〈 i 〉 Background: 〈 /i 〉 Vitamin D receptor activation with paricalcitol can modulate the transcription of renin-angiotensin system components in the surgical 5/6 nephrectomy rat model (5/6 NX) of chronic renal insufficiency. We tested the hypothesis whether dietary modification of phosphate influences kidney renin-angiotensin system gene expression at the mRNA level in 5/6 NX rats. 〈 i 〉 Methods: 〈 /i 〉 Fifteen weeks after surgery, rats were given control diet (0.3% calcium, 0.5% phosphate), phosphate-lowering diet (3% calcium as carbonate) or high-phosphate diet (1.5%) for 12 weeks. Sham-operated rats were on control diet. 〈 i 〉 Results: 〈 /i 〉 Blood pressure, plasma phosphate, parathyroid hormone, glomerulosclerosis, tubulointerstitial damage, and FGF-23 were increased in remnant kidney rats, whereas creatinine clearance was decreased. Phosphate, parathyroid hormone, glomerulosclerosis, tubulointerstitial damage, and FGF-23 were further elevated by the high-phosphate diet, but were reduced by the phosphate-lowering diet. Plasma calcium was increased with the phosphate-lowering diet and decreased with the high-phosphate diet. Remnant kidney rats on control diet showed upregulated kidney angiotensin-converting enzyme (ACE) and angiotensin (Ang) IV receptor (AT 〈 sub 〉 4 〈 /sub 〉 ) transcription, while ACE2, Ang II type 2 receptor and renin receptor transcription were downregulated in comparison with sham rats. Phosphate-lowering diet reduced whereas high-phosphate diet increased kidney ACE, and these effects were observed at both mRNA and protein levels. Dietary phosphate loading also resulted in lower AT 〈 sub 〉 1a 〈 /sub 〉 gene transcription. 〈 i 〉 Conclusion: 〈 /i 〉 Dietary phosphate loading was associated with elevated kidney ACE expression, increased tissue damage and lower AT 〈 sub 〉 1a 〈 /sub 〉 transcription in 5/6 NX rats. Phosphate binding with 3% calcium carbonate had opposite effects on ACE and kidney damage.
    Type of Medium: Online Resource
    ISSN: 0250-8095 , 1421-9670
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2012
    detail.hit.zdb_id: 1468523-1
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  • 3
    In: Journal of Vascular Research, S. Karger AG, Vol. 52, No. 2 ( 2015), p. 94-102
    Abstract: 〈 b 〉 〈 i 〉 Background: 〈 /i 〉 〈 /b 〉 We studied whether vasopeptidase inhibition corrects the structure and function of the small arteries in experimental chronic renal insufficiency (CRI). 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 After 5/6 nephrectomy (NX) surgery was performed on rats, there was a 14-week follow-up, allowing CRI to become established. Omapatrilat (40 mg/kg/day in chow) was then given for 8 weeks, and the small mesenteric arterial rings were investigated in vitro using wire and pressure myographs. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 Plasma and ventricular B-type natriuretic peptide (BNP) concentrations were increased 2- to 2.7-fold, while systolic blood pressure (BP) increased by 32 mm Hg after NX. Omapatrilat treatment normalized the BNP and reduced the BP by 45 mm Hg in the NX rats. Endothelium-dependent vasorelaxation was impaired but the response to acetylcholine was normalized after omapatrilat treatment. Vasorelaxations induced by nitroprusside, isoprenaline and levcromakalim were enhanced after omapatrilat, and the responses were even more pronounced than in untreated sham-operated rats. Arterial wall thickness and wall-to-lumen ratio were increased after NX, whereas omapatrilat normalized these structural features and improved the strain-stress relationship in the small arteries; this suggests improved arterial elastic properties. 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 Omapatrilat treatment reduced BP, normalized volume overload, improved vasorelaxation and corrected the dimensions and passive elastic properties of the small arteries in the NX rats. Therefore, we consider vasopeptidase inhibition to be an effective treatment for CRI-induced changes in the small arteries.
    Type of Medium: Online Resource
    ISSN: 1018-1172 , 1423-0135
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2015
    detail.hit.zdb_id: 1482726-8
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  • 4
    In: BMC Nephrology, Springer Science and Business Media LLC, Vol. 18, No. 1 ( 2017-12)
    Type of Medium: Online Resource
    ISSN: 1471-2369
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2041348-8
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  • 5
    In: Basic & Clinical Pharmacology & Toxicology, Wiley, Vol. 132, No. 1 ( 2023-01), p. 21-32
    Abstract: Uric acid has promoted renal fibrosis and inflammation in experimental studies, but some studies have shown nephroprotective effects due to alleviated oxidative stress. We studied the influence of experimental hyperuricaemia in surgically 5/6 nephrectomized rats. Three weeks after subtotal nephrectomy or sham operation, the rats were allocated to control diet or 2.0% oxonic acid (uricase inhibitor) diet for 9 weeks. Then blood, urine and tissue samples were taken, and renal morphology and oxidative stress were examined. Inflammation and fibrosis were evaluated using immunohistochemistry and real‐time PCR (RT‐PCR). Remnant kidney rats ingesting normal or oxonic acid diet presented with ~60% reduction of creatinine clearance and suppressed plasma renin activity. Oxonic acid diet increased plasma uric acid levels by 〉 80 μmol/L. In remnant kidney rats, moderate hyperuricaemia decreased glomerulosclerosis, tubulointerstitial damage and kidney mast cell count, without influencing the fibrosis marker collagen I messenger RNA (mRNA) content. In both sham‐operated and 5/6 nephrectomized rats, the mast cell product 11‐epi‐prostaglandin‐F 2α excretion to the urine and kidney tissue cyclooxygenase‐2 (COX‐2) levels were decreased. To conclude, hyperuricaemic remnant kidney rats displayed improved kidney morphology and reduced markers of oxidative stress and inflammation. Thus, moderately elevated plasma uric acid had beneficial effects on the kidney in this low‐renin model of experimental renal insufficiency.
    Type of Medium: Online Resource
    ISSN: 1742-7835 , 1742-7843
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2151592-X
    SSG: 15,3
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  • 6
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 3 ( 2020-01-31), p. 936-
    Abstract: Chronic renal insufficiency (CRI) is characterized by increased endothelin 1 (ET-1) synthesis. We studied rat kidney endothelin receptor A (ETA) and receptor B (ETB) expressions after 12 and 27 weeks of 5/6 nephrectomy, and after 12 weeks of 0.3% adenine diet, representing proteinuric and interstitial inflammation models of CRI, respectively. Uric acid and calcium-phosphate metabolism were modulated after 5/6 nephrectomy, while ETA blocker and calcimimetic were given with adenine. Endothelin receptor mRNA levels were measured using RT-qPCR and protein levels using autoradiography (5/6 nephrectomy) or ELISA (adenine model). Both 12 and 27 weeks after 5/6 nephrectomy, kidney cortex ETA protein was increased by ~60% without changes in ETB protein, and the ETB:ETA ratio was reduced. However, the ETB:ETA mRNA ratio did not change. In the adenine model, kidney ETA protein was reduced by ~70%, while ETB protein was suppressed by ~95%, and the ETB:ETA ratio was reduced by ~85%, both at the protein and mRNA levels. The additional interventions did not influence the observed reductions in the ETB:ETA ratio. To conclude, unfavorable reduction in the ETB:ETA protein ratio was observed in two different models of CRI. Therefore, ETA blockade may be beneficial in a range of diseases that cause impaired kidney function.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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