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: Yu Liu, Daniel Flores, Rolando Carrisoza-Gaytán, Rajeev Rohatgi
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 308 Issue 11 Pg. F1229-37 (Jun 01 2015) ISSN: 1522-1466 [Electronic] United States
• PMID: 25761882 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Sodium Chloride
• Cholesterol
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Dinoprostone
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cell Line
• Cholesterol (metabolism)
• Cyclooxygenase 2 (metabolism)
• Dinoprostone (metabolism)
• Ion Transport (physiology)
• Kidney Tubules, Collecting (metabolism)
• MAP Kinase Signaling System (physiology)
• Mice
• Sodium Chloride (metabolism)