title: Antisense inhibition of cyclooxygenase-2 causes a selective suppression of the Na+-H+ exchanger isoform 3 in rat kidney in experimental colitis.
abstract: BACKGROUND
  Experimental colitis induces the expression of Na+-H+ exchanger (NHE) isoforms 1 and 3 in the rat colon, however, their status in rat kidney is not established.
  
  
  OBJECTIVE
  The renal cortical NHE-1 and -3 expression was examined in the colitic rats. Since cyclooxygenase-2 (cox-2) plays an important role in inflammation, its regulatory role on these isoforms was also investigated by using a cox-2-selective phosphorothioated antisense oligonucleotide (S-oligo).
  
  
  METHODS
  Male Sprague-Dawley rats having colitis induced by acetic acid or trinitrobenzenesulfonic acid (TNBS) were given injection of S-oligo (3 mg/kg, i.p.) and a mismatched control oligonucleotide (C-oligo) daily 2 h before inducing colitis. Colonic myeloperoxidase activity (MPO) was used to indicate colitis. The renal cortical levels of NHE-1, NHE-3 and alpha-actin, an internal control, were estimated by the Western blot analysis.
  
  
  RESULTS
  Colonic MPO activity was increased and urine output was decreased in both models of colitis. Serum, but not the renal cortical level of TNF-alpha, was increased in both cases. Only TNBS condition showed an increased PGE2 level and a decreased body weight. Water intake and renal histology remained unchanged in either case. The NHE-3 protein, localized on the proximal tubules, was increased significantly without any change in NHE-1 and alpha-actin in both cases. These changes, except the body weight, were significantly reversed by the S-oligo.
  
  
  CONCLUSIONS
  Selective induction of NHE-3 and TNF-alpha, and their reversal by cox-2 inhibition, suggest a cox-2-dependent regulation of NHE-3, which possibly involves TNF-alpha released from the site of inflammation and not from the kidney in colitis. The induction of NHE-3 is independent of the nature of colitides, and might be important to compensate for the loss of electrolyte and water in experimental colitis.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Kuwait University, Kuwait. Islam@hsc.kuniv.edu.kw
authors.forename: Islam
authors.initials: I
authors.lastname: Khan
mesh_terms: D019342:Acetic Acid; D000818:Animals; D000918:Antibody Specificity; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014563:Urodynamics / Q000187:drug effects
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D016376:Oligonucleotides, Antisense; D017923:Sodium-Hydrogen Exchangers; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D019342:Acetic Acid