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Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPAR?/?-Dependent Vasodilator Pathway.

ABSTRACT: 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 PPAR?/? (peroxisome proliferator-activated receptor-?/?). These data demonstrate the kidney as the principle site in the body where local COX-2 controls blood flow and identifies a previously unreported PPAR?/?-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/PPAR?/? axis as a therapeutic target in renal disease.

SUBMITTER: Kirkby NS

PROVIDER: S-EPMC5770101 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPARβ/δ-Dependent Vasodilator Pathway.

Kirkby Nicholas S NS Sampaio Walkyria W Etelvino Gisele G Alves Daniele T DT Anders Katie L KL Temponi Rafael R Shala Fisnik F Nair Anitha S AS Ahmetaj-Shala Blerina B Jiao Jing J Herschman Harvey R HR Wang Xiaomeng X Wahli Walter W Santos Robson A RA Mitchell Jane A JA

Hypertension (Dallas, Tex. : 1979) 20180102 2

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 ...[more]

PMID: 29295852

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Dataset Information

Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPAR?/?-Dependent Vasodilator Pathway.

Publications

Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPARβ/δ-Dependent Vasodilator Pathway.

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