title: Cyclooxygenase-2 (COX-2) inhibition limits abnormal COX-2 expression and progressive injury in the remnant kidney.
abstract: BACKGROUND
  The pathogenesis of progressive nephropathies involves hemodynamic and inflammatory factors. In the 5/6 nephrectomy model, a selective increase of cyclooxygenase-2 (COX-2) expression was shown, whereas treatment with a nonsteroidal anti-inflammatory or a specific COX-2 inhibitor was renoprotective. We investigated in the 5/6 nephrectomy model (1) the renal distribution of COX-2; (2) the hemodynamic and cellular mechanisms by which chronic COX-2 inhibition prevents renal injury.
  
  
  METHODS
  After 5/6 nephrectomy, adult male Munich-Wistar rats were subdivided in two groups: 5/6 nephrectomy (N=20), receiving vehicle, and 5/6 nephrectomy + celecoxib (N=19), treated orally with the COX-2 inhibitor, celecoxib, 10 mg/kg/day. Untreated and treated (celecoxib) sham-operated rats were also studied. Renal hemodynamics were examined at 4 weeks, whereas renal morphologic/immunohistochemical studies were carried at 8 weeks.
  
  
  RESULTS
  At 4 weeks, 5/6 nephrectomy rats exhibited marked systemic and glomerular hypertension. Celecoxib attenuated both systemic and glomerular hypertension, without affecting glomerular filtration rate (GFR). At 8 weeks, glomerulosclerosis and interstitial expansion were evident in 5/6 nephrectomy rats, and markedly attenuated in 5/6 nephrectomy rats given celecoxib. In both sham-operated and 5/6 nephrectomy rats, COX-2 was expressed at the macula densa. The extent of COX-2 expression at the macula densa was nearly tripled by celecoxib, indicating the existence of a feedback mechanism. In 5/6 nephrectomy rats, COX-2 was also expressed in glomeruli, arterioles, and the cortical interstitium, mostly at inflamed or sclerosing areas. Celecoxib markedly attenuated renal injury, inflammation, and ectopic COX-2 expression in 5/6 nephrectomy rats.
  
  
  CONCLUSIONS
  Chronic COX-2 inhibition attenuated progressive nephropathy by reducing glomerular hypertension, renal inflammation, and ectopic COX-2 expression, indicating a complex contribution of COX-2 to progressive renal injury in 5/6 nephrectomy rats.
authors: Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
authors: Clarice Kazue
authors: CK
authors: Fujihara
authors: Gláucia Rutigliano
authors: GR
authors: Antunes
authors: Ana Lúcia
authors: AL
authors: Mattar
authors: Natalie
authors: N
authors: Andreoli
authors: Denise Maria Avancini Costa
authors: DM
authors: Malheiros
authors: Irene Lourdes
authors: IL
authors: Noronha
authors: Roberto
authors: R
authors: Zatz
mesh_terms: D000818:Animals; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D018450:Disease Progression; D006439:Hemodynamics / Q000187:drug effects; D006977:Hypertension, Renal / Q000503:physiopathology; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007668:Kidney / Q000201:enzymology* / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus; D008297:Male; D009392:Nephrectomy / Q000009:adverse effects / Q000379:methods*; D009393:Nephritis / Q000473:pathology; D011184:Postoperative Period; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib