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@article{Kirkby:2018:10.1161/HYPERTENSIONAHA.117.09906,
author = {Kirkby, NS and Sampaio, W and Etelvino, G and Alves, D and Anders, KL and Temponi, R and Shala, F and Nair, AS and Ahmetaj-Shala, B and Jiao, J and Herschman, HR and Xiaomeng, W and Wahli, W and Santos, RA and Mitchell, JA},
doi = {10.1161/HYPERTENSIONAHA.117.09906},
journal = {Hypertension},
pages = {297--305},
title = {Cyclooxygenase-2 selectively controls renal blood flow through a novel PPARβ/δ-dependent renal vasodilator pathway},
url = {http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09906},
volume = {71},
year = {2018}
}

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TY  - JOUR
AB  - Cyclooxygenase-2 (COX-2) is an inducible enzyme expressed in inflammation and cancer targeted by nonsteroidal anti-inflammatory drugs. COX-2 is also expressed constitutively in discreet locations where its inhibition drives gastrointestinal and cardiovascular/renal side effects. Constitutive COX-2 expression in the kidney regulates renal function and blood flow; however, the global relevance of the kidney versus other tissues to COX-2–dependent blood flow regulation is not known. Here, we used a microsphere deposition technique and pharmacological COX-2 inhibition to map the contribution of COX-2 to regional blood flow in mice and compared this to COX-2 expression patterns using luciferase reporter mice. Across all tissues studied, COX-2 inhibition altered blood flow predominantly in the kidney, with some effects also seen in the spleen, adipose, and testes. Of these sites, only the kidney displayed appreciable local COX-2 expression. As the main site where COX-2 regulates blood flow, we next analyzed the pathways involved in kidney vascular responses using a novel technique of video imaging small arteries in living tissue slices. We found that the protective effect of COX-2 on renal vascular function was associated with prostacyclin signaling through PPARβ/δ (peroxisome proliferator-activated receptor-β/δ). These data demonstrate the kidney as the principle site in the body where local COX-2 controls blood flow and identifies a previously unreported PPARβ/δ-mediated renal vasodilator pathway as the mechanism. These findings have direct relevance to the renal and cardiovascular side effects of drugs that inhibit COX-2, as well as the potential of the COX-2/prostacyclin/PPARβ/δ axis as a therapeutic target in renal disease.
AU  - Kirkby,NS
AU  - Sampaio,W
AU  - Etelvino,G
AU  - Alves,D
AU  - Anders,KL
AU  - Temponi,R
AU  - Shala,F
AU  - Nair,AS
AU  - Ahmetaj-Shala,B
AU  - Jiao,J
AU  - Herschman,HR
AU  - Xiaomeng,W
AU  - Wahli,W
AU  - Santos,RA
AU  - Mitchell,JA
DO  - 10.1161/HYPERTENSIONAHA.117.09906
EP  - 305
PY  - 2018///
SN  - 0194-911X
SP  - 297
TI  - Cyclooxygenase-2 selectively controls renal blood flow through a novel PPARβ/δ-dependent renal vasodilator pathway
T2  - Hypertension
UR  - http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09906
UR  - http://hdl.handle.net/10044/1/54538
VL  - 71
ER  -

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