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Local Purinergic Control of Arteriolar Reactivity in Pancreatic Islets and Renal Glomeruli
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Local control of regional blood flow is exerted mainly through the arterioles. An adequate minute-to-minute regulation of blood perfusion of the kidney and the pancreas is obtained by the modulation of arteriolar reactivity, which will influence the organ function. The importance of purinergic signaling in this concept has been addressed, with special emphasis on the role of the adenosine A1 receptor. The effects of adenosine on two specialized vascular beds, namely the renal glomerulus and the pancreatic islets, have been examined. Characteristic for these regional circulations is their very high basal blood flow, but with somewhat different responses to vasoconstrictor and vasodilator stimuli. By adapting a unique microperfusion technique it was possible to separately perfuse isolated single mouse arterioles with attached glomeruli or pancreatic islets ex vivo. Microvascular responses were investigated following different additions to the perfusion fluid to directly examine the degree of dilation or constriction of the arterioles. This has been performed on transgenic animals in this thesis, e.g. A1 receptor knockout mice. Also effects of P2Y receptors on islet arterioles were examined in both normoglycemic and type 2 diabetic rats. Furthermore, interference with adenosine transport in glomerular arterioles were examined.. Our studies demonstrate important, yet complex, effects of adenosine and nucleotide signaling on renal and islet microvascular function, which in turn may influence both cardiovascular and metabolic regulations. They highlight the need for further studies of other purinergic receptors in this context, studies that are at currently being investigated.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1024
Keyword [en]
afferent arteriole, islet arteriole, adenosine, A1 receptor, ATP, P2Y receptor, microperfusion, angiotensin II, type 2 diabetes, hypertension, oxidative stress, nitric oxide, tubuloglomerular feedback
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-230770ISBN: 978-91-554-9018-8 (print)OAI: oai:DiVA.org:uu-230770DiVA: diva2:741740
Public defence
2014-10-16, C2: 301, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2014-09-24 Created: 2014-08-28 Last updated: 2015-01-22
List of papers
1. Adenosine A(1)-receptor deficiency diminishes afferent arteriolar and blood pressure responses during nitric oxide inhibition and angiotensin II treatment
Open this publication in new window or tab >>Adenosine A(1)-receptor deficiency diminishes afferent arteriolar and blood pressure responses during nitric oxide inhibition and angiotensin II treatment
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2011 (English)In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 301, no 6, R1669-R1681 p.Article in journal (Refereed) Published
Abstract [en]

Adenosine mediates tubuloglomerular feedback responses via activation of A(1)-receptors on the renal afferent arteriole. Increased preglomerular reactivity, due to reduced nitric oxide (NO) production or increased levels of ANG II and reactive oxygen species (ROS), has been linked to hypertension. Using A(1)-receptor knockout (A(1)(-/-)) and wild-type (A(1)(+/+)) mice we investigated the hypothesis that A(1)-receptors modulate arteriolar and blood pressure responses during NO synthase (NOS) inhibition or ANG II treatment. Blood pressure and renal afferent arteriolar responses were measured in nontreated mice and in mice with prolonged N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME) or ANG II treatment. The hypertensive responses to L-NAME and ANG II were clearly attenuated in A(1)(-/-) mice. Arteriolar contractions to L-NAME (10(-4) mol/l; 15 min) and cumulative ANG II application (10(-12) to 10(-6) mol/l) were lower in A(1)(-/-) mice. Simultaneous treatment with tempol (10(-4) mol/l; 15 min) attenuated arteriolar responses in A(1)(+/+) but not in A(1)(-/-) mice, suggesting differences in ROS formation. Chronic treatment with L-NAME or ANG II did not alter arteriolar responses in A(1)(-/-) mice, but enhanced maximal contractions in A(1)(+/+) mice. In addition, chronic treatments were associated with higher plasma levels of dimethylarginines (asymmetrical and symmetrical) and oxidative stress marker malondialdehyde in A(1)(+/+) mice, and gene expression analysis showed reduced upregulation of NOS-isoforms and greater upregulation of NADPH oxidases. In conclusion, adenosine A(1)-receptors enhance preglomerular responses during NO inhibition and ANG II treatment. Interruption of A(1)-receptor signaling blunts L-NAME and ANG II-induced hypertension and oxidative stress and is linked to reduced responsiveness of afferent arterioles.

Keyword
preglomerular function, hypertension, oxidative stress, tubuloglomerular feedback, reactive oxygen species
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-167644 (URN)10.1152/ajpregu.00268.2011 (DOI)000298176700007 ()
Available from: 2012-02-01 Created: 2012-01-31 Last updated: 2017-12-08Bibliographically approved
2. Adenosine A1 receptor-dependent and independent pathways in modulating renal vascular responses to angiotensin II
Open this publication in new window or tab >>Adenosine A1 receptor-dependent and independent pathways in modulating renal vascular responses to angiotensin II
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2015 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 1, 268-276 p.Article in journal (Refereed) Published
Abstract [en]

AIM: Renal afferent arterioles are the effector site for autoregulation of glomerular perfusion and filtration. There is synergistic interaction between angiotensin II (ANG II) and adenosine (Ado) in regulating arteriolar contraction, however, the mechanisms are not clear. In this context, this study investigated the contribution of A1 receptor dependent and independent signaling mechanisms.

METHODS: Isolated perfused afferent arterioles from transgenic mice (A1+/+ and A1-/-) were used for vascular reactivity studies. Cultured vascular smooth muscle cells (VSMC) were used for phosphorylation studies of signaling proteins that induce arteriolar contraction.

RESULTS: Maximal arteriolar contraction to ANG II was attenuated in A1-/- (22%) compared with A1+/+ (40%). Simultaneous incubation with low dose Ado (10-8 mol/L) enhanced ANG II-induced contraction in A1+/+ (58%), but also in A1-/- (42%). An Ado transporter inhibitor (NBTI) abolished this synergistic effect in A1-/-, but not in wild-type mice. Incubation with Ado+ANG II increased p38 phosphorylation in aortic VSMC from both genotypes, but treatment with NBTI only blocked phosphorylation in A1-/-. Combination of ANG II+Ado also increased MLC phosphorylation in A1+/+ but not significantly in A1-/-, and NBTI had no effects. In agreement, Ado+ANG II-induced phosphorylation of p38 and MLC in rat preglomerular VSMC was not affected by NBTI. However, during pharmacological inhibition of the A1 receptor simultaneous treatment with NBTI reduced phosphorylation of both p38 and MLC to control levels.

CONCLUSION: Interaction between ANG II and Ado in VSMC normally involves A1 receptor signaling, but this can be compensated by receptor independent actions that phosphorylate p38 MAPK and MLC.

Keyword
afferent arteriole, microcirculation, vascular smooth muscle cell, kidney, p38 MAP kinase, myosin light chain
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-230758 (URN)10.1111/apha.12399 (DOI)000346475000021 ()
Available from: 2014-08-28 Created: 2014-08-28 Last updated: 2017-12-05Bibliographically approved
3. Abrogation of adenosine A1 receptor signaling improves metabolic regulation in mice by modulating oxidative stress and inflammatory responses
Open this publication in new window or tab >>Abrogation of adenosine A1 receptor signaling improves metabolic regulation in mice by modulating oxidative stress and inflammatory responses
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(English)Manuscript (preprint) (Other academic)
Keyword
type 2 diabetes, visceral adipose tissue, metabolic syndrome, insulin resistance, islet arterioles, inflammation and oxidative stress
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-230766 (URN)
Note

Aims/hypothesis: Adenosine is an important regulator of metabolism, however, the role of A1receptor during aging and obesity is unclear. This study aimed at investigating the effects ofA1 signaling in modulating the metabolic function during aging. Methods: Age-matched young and aged A1-knockout (A1-/-) and wild-type (A1+/+) mice wereused. Metabolic regulation was evaluated by body composition, glucose and insulin tolerancetests. Isolated islets and islet arterioles were used to detect islet endocrine and vascularfunction. Oxidative stress and inflammation status were measured in metabolic organs andsystemically. Results: Advanced age was associated with reduced glucose clearance and insulin sensitivity, and increased white adipose tissue (VAT) in A1+/+ compared to A1-/- mice. Islet morphologyand insulin content were similar between genotypes, but relative changes in in vitro insulinrelease following glucose stimulation were reduced in aged A1+/+ compared with A1-/- mice.Islet arteriolar responses to angiotensin II were stronger in aged A1+/+ mice, this beingassociated with increased NADPH oxidase activity. Aging resulted in multiple changes inA1+/+ compared with A1-/- mice, including enhanced O2- formation in pancreas and VAT,elevated levels of circulating insulin, leptin and pro-inflammatory cytokines (TNF-α, IL-1β,IL-6 & IL-12) and accumulation of CD4+ T-cells in VAT. This was associated with impairedinsulin signaling in VAT from aged A1+/+ mice. Conclusions/interpretations: These studies emphasize that A1 receptors regulate metabolismand islet endocrine and vascular functions during aging by modulating oxidative stress andinflammatory responses.

Available from: 2014-08-28 Created: 2014-08-28 Last updated: 2015-01-22
4. Important role of P2Y receptors for islet blood flow regulation in anesthetized rats during acute and chronic hyperglycemia
Open this publication in new window or tab >>Important role of P2Y receptors for islet blood flow regulation in anesthetized rats during acute and chronic hyperglycemia
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Pancreatic islet blood flow is regulated through a complex interplay between nervous, metabolic and local endothelial factors. We have previously shown that adenosine is an important vasodilator in the metabolic regulation of islet blood flow and now wanted to examine whether also ATP/ADP/AMP could affect islet blood perfusion through P2Y receptors. To achieve this we examined local blood flow values in normoglycemic and acutely hyperglycemic Sprague-Dawley rats as well as GK rats, a type 2 diabetes model. We inhibited P2Y receptors in general with suramine and, since P2Y13 receptors are known to inhibit insulin secretion, we also examined the effects of a selective P2Y13 receptor inhibitor, viz. MRS2211. We found that all GK rats were hyperglycemic and hypertensive when compared to SD rats. Basal islet blood flow in SD rats was decreased by MRS2211, and there was a trend for this to occur also after suramine administration. The glucose-induced islet blood flow increase in SD rats was impaired after suramine and MRS2211 treatment. GK rats had higher islet blood flow, but not islet vascular conductance, than SD rats, which did not react to acute hyperglycemia or the P2Y receptor inhibitors. Similar findings were made in an islet arteriole perfusion model, suggesting that local P2Y receptors are involved. A surprising finding was that especially suramine markedly increased colonic blood flow in SD rats, and decreased this blood flow in GK rats. We conclude that not only adenosine, but also also ATP and especially ADP stimulate both basal and glucose-stimulated islet blood flow in anesthetized SD rats, but this response is not seen in GK rats. Also colonic blood flow seems to be sensitive to P2Y receptors and increase its blood flow when these receptors are inhibited. The mechanisms behind this are unknown.

Keyword
Pancreatic islets, Islet blood flow, Islet arterioles, Colonic blood flow, P2Y receptors
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-230768 (URN)
Available from: 2014-08-28 Created: 2014-08-28 Last updated: 2015-01-22

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