Biomechanical regulation of cyclooxygenase-2 in the renal collecting duct.
High-dietary sodium (Na), a feature of the Western diet, requires the kidney to excrete ample Na to maintain homeostasis and prevent hypertension. High urinary flow rate, presumably, leads to an increase in fluid shear stress (FSS) and FSS-mediated release of prostaglandin E2 (PGE2) by the cortical collecting duct (CCD) that enhances renal Na excretion. The pathways by which tubular flow biomechanically regulates PGE2 release and cyclooxygenase-2 (COX-2) expression are limited. We hypothesized that FSS, through stimulation of neutral-sphingomyelinase (N-SM) activity, enhances COX-2 expression to boost Na excretion. To test this, inner medullary CD3 cells were exposed to FSS in vitro and mice were injected with isotonic saline in vivo to induce high tubular flow. In vitro, FSS induced N-SM activity and COX-2 protein expression in cells while inhibition of N-SM activity repressed FSS-induced COX-2 protein abundance. Moreover, the murine CCD expresses N-SM protein and, when mice are injected with isotonic saline to induce high tubular flow, renal immunodetectable COX-2 is induced. Urinary PGE2 (445 ± 91 vs. 205 ± 14 pg/ml; P < 0.05) and microdissected CCDs (135.8 ± 21.7 vs. 65.8 ± 11.0 pg·ml(-1)·mm(-1) CCD; P < 0.05) from saline-injected mice generate more PGE2 than sham-injected controls, respectively. Incubation of CCDs with arachidonic acid and subsequent measurement of secreted PGE2 are a reflection of the PGE2 generating potential of the epithelia. CCDs isolated from polyuric mice doubled their PGE2 generating potential and this was due to induction of COX-2 activity/protein. Thus, high tubular flow and FSS induce COX-2 protein/activity to enhance PGE2 release and, presumably, effectuate Na excretion.
One Gustave L. Levy Place, Box 1664, The Mount Sinai School of Medicine, New York, NY 10029. rajeev.rohatgi@mssm.edu.
Yu
Y
Liu
Daniel
D
Flores
Rolando
R
Carrisoza-Gaytán
Rajeev
R
Rohatgi
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001696:Biomechanical Phenomena / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004848:Epithelium / Q000502:physiology; D005455:Fluorescent Antibody Technique; D007685:Kidney Tubules, Collecting / Q000201:enzymology*; D008297:Male; D050527:Mesangial Cells / Q000502:physiology; D051379:Mice; D033081:Shear Strength; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D013108:Sphingomyelin Phosphodiesterase; D015232:Dinoprostone
cation transport; cyclooxygenase; fluid shear stress; prostaglandin E2; prostanoid