Cyclooxygenase-2 selectively controls renal blood flow through a novel pparβ/δ-dependent vasodilator pathway

• Main Authors: Shala, Fisnik, Nair, Anitha S., Ahmetaj-Shala, Blerina, Jiao, Jing, Kirkby, Nicholas S., Sampaio, Walkyria, Etelvino, Gisele, Alves, Daniele T., Anders, Katie L., Temponi, Rafael, Herschman, Harvey R., Wang, Xiaomeng, Wahli, Walter, Santos, Robson A., Mitchell, Jane A.
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2018
• Subjects: Endothelium; Cyclooxygenase 2; DRNTU::Science::Medicine
• Online Access: https://hdl.handle.net/10356/89772; http://hdl.handle.net/10220/46357
• Institution: Nanyang Technological University

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.