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Renal denervation attenuates NADPH oxidase-mediated oxidative stress and hypertension in rats with hydronephrosis
Dept of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Barnkirurgi/Christofferson)
Dept of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2016 (English)In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 310, no 1, p. F43-F56Article in journal (Refereed) Published
Abstract [en]

Hydronephrosis is associated with development of salt-sensitive hypertension. Studies suggest that increased sympathetic nerve activity (SNA) and oxidative stress play important roles in renovascular hypertension. This study aimed to investigate the link between renal SNA and NADPH oxidase (NOX) regulation in the development of hypertension in rats with hydronephrosis. Hydronephrosis was induced by partial unilateral ureteral obstruction (PUUO) in young rats. Sham surgery or renal denervation was performed at the same time. Blood pressure was measured during normal, high and low salt diets. Renal excretion pattern, NOX activity and expression, as well as components of RAAS were characterized. On normal salt diet, PUUO rats had elevated blood pressure compared with controls (115±3 vs 87±1 mmHg), and displayed increased urine production and lower urine osmolality. Blood pressure change in response to salt loading (salt-sensitivity) was more pronounced in the PUUO group compared with controls (15±2 vs 5±1mmHg). Renal denervation in PUUO rats attenuated hypertension (97±3mmHg) and salt-sensitivity (5±1mmHg), and normalized renal excretion pattern, whereas the degree of renal fibrosis and inflammation was not changed. NOX activity and expression, as well as renin and AT1A receptor expression, were increased in renal cortex from PUUO rats, and normalized by denervation. Plasma sodium and potassium levels were elevated in PUUO rats and normalized after renal denervation. Denervation in PUUO rats was also associated with reduced NOX expression, superoxide production and fibrosis in the heart. This study emphasizes a link between renal nerves, NOX function, and development of hypertension.

Place, publisher, year, edition, pages
2016. Vol. 310, no 1, p. F43-F56
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-267780DOI: 10.1152/ajprenal.00345.2015ISI: 000366593500007PubMedID: 26538440OAI: oai:DiVA.org:uu-267780DiVA, id: diva2:874285
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2015-11-26 Created: 2015-11-26 Last updated: 2018-01-22Bibliographically approved
In thesis
1. High Blood Pressure in Children with Hydronephrosis
Open this publication in new window or tab >>High Blood Pressure in Children with Hydronephrosis
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The most common cause of secondary hypertension is intrinsic renal disease, but little is known about the influence of hydronephrosis on blood pressure. In this thesis, the risk of development of hypertension in children with hydronephrosis was studied.

Experimental and clinical studies were combined in order to investigate the risk of developing elevated blood pressure following conservative treatment of hydronephrosis, and to further explore underlying mechanisms. We started with a clinical study in children (study I), which in agreement with previous experimental studies, showed that blood pressure was lowered by surgical management of hydronephrosis. In parallel, an experimental study was conducted (study II) to investigate the involvement of renal sympathetic nerve activity in development of hypertension following induction of hydronephrosis caused by pelvo-ureteric junction obstruction. Renal denervation of the obstructed kidney attenuated hypertension and restored the renal excretion pattern, effects that were associated with reduced activity of both renal NADPH oxidase derived oxidative stress and components of the renin-angiotensin-aldosterone system.

Based on the findings in studies I and II, we continued our studies in children with hydronephrosis, and including two control groups as comparisons with the hydronephrotic group (study III). In the same study, we further investigated potential mechanism(s) of hypertension by analyzing markers of oxidative stress and nitric oxide homeostasis in both urine and blood samples. We demonstrated increased arterial pressure and oxidative stress in children with hydronephrosis compared with healthy controls, which was restored to normal levels by surgical correction of the obstruction. Finally, in a retrospective cohort study, blood pressure of adult patients undergoing surgical management of hydronephrosis due to pelvo-ureteric junction obstruction was assessed (study IV). Similar to that demonstrated in the pediatric hydronephrotic population, blood pressure was significantly reduced by relief of the obstruction. In addition, blood pressure was increased again if the hydronephrosis recurred, and was reduced again following re-operation.

It is concluded that conservative management of hydronephrosis in children is associated with a risk for development of high blood pressure, which can be reduced or even normalized by relief of the obstruction. The mechanism(s), at least in part, is coupled to increased oxidative stress.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 71
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1417
Keywords
Blood pressure, hydronephrosis, hypertension, ambulatory blood pressure monitoring, nitric oxide, oxidative stress, pelvo-ureteric junction obstruction.
National Category
Pediatrics
Research subject
Pediatric Surgery
Identifiers
urn:nbn:se:uu:diva-338678 (URN)978-91-513-0206-5 (ISBN)
Public defence
2018-03-01, Rosénsalen, Akademiska barnsjukhuset ingång 95-96, Uppsala, 13:15 (English)
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Available from: 2018-02-07 Created: 2018-01-11 Last updated: 2018-03-08

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Al-Mashhadi, Ammar Nadhom FarmanPersson, A Erik G

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