Cellular cholesterol modifies flow-mediated gene expression

Am J Physiol Renal Physiol. 2019 Oct 1;317(4):F815-F824. doi: 10.1152/ajprenal.00196.2019. Epub 2019 Jul 31.


Downregulation of heme oxygenase-1 (HO-1), cyclooxygenase-2 (COX2), and nitric oxide synthase-2 (NOS2) in the kidneys of Dahl rodents causes salt sensitivity, while restoring their expression aids in Na+ excretion and blood pressure reduction. Loading cholesterol into collecting duct (CD) cells represses fluid shear stress (FSS)-mediated COX2 activity. Thus, we hypothesized that cholesterol represses flow-responsive genes necessary to effectuate Na+ excretion. To this end, CD cells were used to test whether FSS induces these genes and if cholesterol loading represses them. Mice fed either 0% or 1% cholesterol diet were injected with saline, urine volume and electrolytes were measured, and renal gene expression determined. FSS-exposed CD cells demonstrated increases in HO-1 mRNA by 350-fold, COX2 by 25-fold, and NOS2 by 8-fold in sheared cells compared with static cells (P < 0.01). Immunoblot analysis of sheared cells showed increases in HO-1, COX2, and NOS2 protein, whereas conditioned media contained more HO-1 and PGE2 than static cells. Cholesterol loading repressed the sheared mediated protein abundance of HO-1 and NOS2 as well as HO-1 and PGE2 concentrations in media. In cholesterol-fed mice, urine volume was less at 6 h after injection of isotonic saline (P < 0.05). Urinary Na+ concentration, urinary K+ concentration, and osmolality were greater, whereas Na+ excretion was less, at the 6-h urine collection time point in cholesterol-fed versus control mice (P < 0.05). Renal cortical and medullary HO-1 (P < 0.05) and NOS2 (P < 0.05) mRNA were repressed in cholesterol-fed compared with control mice. Cholesterol acts to repress flow induced natriuretic gene expression, and this effect, in vivo, may contribute to renal Na+ avidity.

Keywords: blood pressure; collecting duct; flow; shear.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blood Pressure
  • Cell Line
  • Cholesterol / pharmacology*
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / metabolism
  • Gene Expression / drug effects*
  • Heme Oxygenase (Decyclizing) / metabolism
  • Kidney / drug effects*
  • Kidney / metabolism*
  • Kidney Tubules, Collecting / metabolism
  • Mice
  • Nitric Oxide Synthase Type II / metabolism
  • Potassium / urine
  • Rats
  • Rats, Inbred Dahl
  • Sodium / urine
  • Sodium Chloride, Dietary
  • Urodynamics / drug effects


  • Sodium Chloride, Dietary
  • Cholesterol
  • Sodium
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Heme Oxygenase (Decyclizing)
  • Hmox1 protein, rat
  • Cyclooxygenase 2
  • Ptgs2 protein, rat
  • Dinoprostone
  • Potassium