Cholesterol affects flow-stimulated cyclooxygenase-2 expression and prostanoid secretion in the cortical collecting duct.

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 E-2 (PGE(2)), 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 PGE(2) release was measured. Secreted PGE2 was similar between no-and low-flow (151 +/- 28 vs. 121 +/- 48 pg.ml(-1).mm(-1)) CCDs, but PGE(2) 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 PGE(2) secretion. CCDs isolated from cholesterol-fed mice secreted less PGE(2) and had a lower PGE(2)-generating capacity than CCDs isolated from control mice, implying cholesterol repressed flow-induced PGE(2) synthesis. Next, cholesterol extraction in a CD cell line induced COX-2 expression and PGE(2) 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 PGE(2) release via a p38-dependent mechanism.