Cyclooxygenase-2 (COX-2) inhibition limits abnormal COX-2 expression and progressive injury in the remnant kidney.
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.
Fujihara
Clarice Kazue
CK
Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
Antunes
Gláucia Rutigliano
GR
Mattar
Ana Lúcia
AL
Andreoli
Natalie
N
Malheiros
Denise Maria Avancini Costa
DM
Noronha
Irene Lourdes
IL
Zatz
Roberto
R
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
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib