title: Cholesterol affects flow-stimulated cyclooxygenase-2 expression and prostanoid secretion in the cortical collecting duct.
abstract: Essential hypertension (eHTN) is associated with hypercholesterolemia, but how cholesterol contributes to eHTN is unknown. Recent evidence demonstrates that short-term dietary cholesterol ingestion induces epithelial Na channel (ENaC)-dependent Na absorption with a subsequent rise in blood pressure (BP), implicating cholesterol in salt-sensitive HTN. Prostaglandin E2 (PGE2), an autocrine/paracrine molecule, is induced by flow in endothelia to vasodilate the vasculature and inhibit ENaC-dependent Na absorption in the renal collecting duct (CD), which reduce BP. We hypothesize that cholesterol suppresses flow-mediated cyclooxygenase-2 (COX-2) expression and PGE2 release in the CD, which, in turn, affects Na absorption. Cortical CDs (CCDs) were microperfused at 0, 1, and 5 nl·min(-1)·mm(-1), and PGE2 release was measured. Secreted PGE2 was similar between no- and low-flow (151 ± 28 vs. 121 ± 48 pg·ml(-1)·mm(-1)) CCDs, but PGE2 was greatest from high-flow (578 ± 146 pg·ml(-1)·mm(-1); P < 0.05) CCDs. Next, mice were fed either a 0 or 1% cholesterol diet, injected with saline to generate high urine flow rates, and CCDs were microdissected for PGE2 secretion. CCDs isolated from cholesterol-fed mice secreted less PGE2 and had a lower PGE2-generating capacity than CCDs isolated from control mice, implying cholesterol repressed flow-induced PGE2 synthesis. Next, cholesterol extraction in a CD cell line induced COX-2 expression and PGE2 release while cholesterol incorporation, conversely, suppressed their expression. Moreover, fluid shear stress (FSS) and cholesterol extraction induced COX-2 protein abundance via p38-dependent activation. Thus cellular cholesterol composition affects biomechanical signaling, which, in turn, affects FSS-mediated COX-2 expression and PGE2 release via a p38-dependent mechanism.
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medicine, The James J. Peters Veterans Affairs Medical Center, New York, New York; and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medicine, The James J. Peters Veterans Affairs Medical Center, New York, New York; and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Flores
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Rolando
authors.initials: R
authors.lastname: Carrisoza-Gaytán
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medicine, The James J. Peters Veterans Affairs Medical Center, New York, New York; and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York rajeev.rohatgi@mssm.edu.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Rohatgi
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D017136:Ion Transport / Q000502:physiology; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D012965:Sodium Chloride / Q000378:metabolism
chemical_list: D012965:Sodium Chloride; D002784:Cholesterol; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D002118:Calcium
keywords: cholesterol; collecting duct; shear