Details
| Original language | English |
|---|---|
| Pages (from-to) | 1770-1778 |
| Number of pages | 9 |
| Journal | Kidney International |
| Volume | 56 |
| Issue number | 5 |
| Early online date | 1 Nov 1999 |
| Publication status | Published - 1999 |
| Externally published | Yes |
Abstract
Background. Nonsteroidal anti-inflammatory drugs (NSAIDs) induce an inhibition of cyclooxygenase (COX), an enzyme that makes prostaglandins. Two isoforms of COX exist: COX-1 represents the constitutively expressed enzyme, whereas COX-2 is the inducible isoform. This study investigated the role of COX-2 in the inflammatory processes of the kidneys of rats with passive Heymann nephritis (PHN), and focused of the effect of a selective COX-2 inhibitor, flosulide. COX-2-selective inhibitors are thought to represent potent anti-inflammatory agents without major renal side effects. Methods. PHN was induced by injecting heterologous Fx1A antiserum into female Wistar rats. Two treatment groups, each consisting of 12 rats with PHN, received either 3 or 9 mg of flosulide/kg body wt/day and were compared with untreated controls. After four weeks, the generation of thromboxane B2 (TxB2) and 6- keto-PGF(1α) were determined in renal tissue and in urine. COX-2 protein expression was investigated by Western blotting using a selective antibody. Results. Rats with PHN exhibited a marked proteinuria of 71 ± 8 mg/24 hr as compared with 2.0 ± 0.3 mg/24 hr in healthy controls (P < 0.01). Treatment with flosulide reduced the proteinuria to 26.1 ± 9 mg/24 hr at 3 mg flosulide/kg body wt/day and 35.5 ± 6 mg/24 hr at 9 mg/kg body wt/day, which was equivalent to a reduction of proteinuria by a maximum of 65% (P < 0.05). This was accompanied by an increase in glomerular TxB2 from 3073 ± 355 to 5255 ± 1041 pg/mg glomerular protein and 6-keto-PGF(1α) from 1702 ± 161 to 2724 ± 770 pg/mg glomerular protein in rats with PHN. COX-2 protein expression was also highly elevated in comparison to healthy controls. Low- dose flosulide treatment had no effect on COX protein expression and renal prostaglandin formation. High-dose flosulide treatment reduced renal prostaglandin production and caused a marked decline in COX-1 and COX-2 protein expression. Urine prostanoid excretion remained unchanged in all therapeutic groups. There was a small though significant reduction in renal creatinine clearance from 0.86 ml ± 0.2/min in untreated controls to 0.6 ml ± 0.1/min in flosulide-treated rats with PHN (P < 0.01) after four weeks. Conclusions. Under the influence of flosulide, a highly COX-2-selective inhibitor, we observed an antiproteinuric drug effect. The inflammation in PHN induced COX-2 protein expression that was not affected by low-dose flosulide. COX-1 and COX-2 protein expression was affected by high-dose flosulide, which therefore might lose its selectivity. High-dose flosulide induced a decrease in glomerular prostanoid production possibly because of COX-1 inhibition. Our results suggest that the therapeutic use of flosulide in proteinuria seems advantageous and deserves further studies because the basal prostaglandin levels remain unchanged in the low-dose-treated group, indicating that the compensatory capacity of prostaglandin production, which is essential for the regulation of renal hemodynamics, is maintained.
Keywords
- Cyclooxygenase, Kidney, NSAIDs, Proteinuria, Renal hemodynamics, Thromboxane A
ASJC Scopus subject areas
- Medicine(all)
- Nephrology
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In: Kidney International, Vol. 56, No. 5, 1999, p. 1770-1778.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Effect of flosulide, a selective cyclooxygenase 2 inhibitor, on passive Heymann nephritis in the rat
AU - Blume, Cornelia
AU - Heise, Gunhild
AU - Mühlfeld, Anja
AU - Bach, Dieter
AU - Schrör, Rarsten
AU - Gerhardz, Claus Dieter
AU - Grabensee, Bernd
AU - Heering, Peter
PY - 1999
Y1 - 1999
N2 - Background. Nonsteroidal anti-inflammatory drugs (NSAIDs) induce an inhibition of cyclooxygenase (COX), an enzyme that makes prostaglandins. Two isoforms of COX exist: COX-1 represents the constitutively expressed enzyme, whereas COX-2 is the inducible isoform. This study investigated the role of COX-2 in the inflammatory processes of the kidneys of rats with passive Heymann nephritis (PHN), and focused of the effect of a selective COX-2 inhibitor, flosulide. COX-2-selective inhibitors are thought to represent potent anti-inflammatory agents without major renal side effects. Methods. PHN was induced by injecting heterologous Fx1A antiserum into female Wistar rats. Two treatment groups, each consisting of 12 rats with PHN, received either 3 or 9 mg of flosulide/kg body wt/day and were compared with untreated controls. After four weeks, the generation of thromboxane B2 (TxB2) and 6- keto-PGF(1α) were determined in renal tissue and in urine. COX-2 protein expression was investigated by Western blotting using a selective antibody. Results. Rats with PHN exhibited a marked proteinuria of 71 ± 8 mg/24 hr as compared with 2.0 ± 0.3 mg/24 hr in healthy controls (P < 0.01). Treatment with flosulide reduced the proteinuria to 26.1 ± 9 mg/24 hr at 3 mg flosulide/kg body wt/day and 35.5 ± 6 mg/24 hr at 9 mg/kg body wt/day, which was equivalent to a reduction of proteinuria by a maximum of 65% (P < 0.05). This was accompanied by an increase in glomerular TxB2 from 3073 ± 355 to 5255 ± 1041 pg/mg glomerular protein and 6-keto-PGF(1α) from 1702 ± 161 to 2724 ± 770 pg/mg glomerular protein in rats with PHN. COX-2 protein expression was also highly elevated in comparison to healthy controls. Low- dose flosulide treatment had no effect on COX protein expression and renal prostaglandin formation. High-dose flosulide treatment reduced renal prostaglandin production and caused a marked decline in COX-1 and COX-2 protein expression. Urine prostanoid excretion remained unchanged in all therapeutic groups. There was a small though significant reduction in renal creatinine clearance from 0.86 ml ± 0.2/min in untreated controls to 0.6 ml ± 0.1/min in flosulide-treated rats with PHN (P < 0.01) after four weeks. Conclusions. Under the influence of flosulide, a highly COX-2-selective inhibitor, we observed an antiproteinuric drug effect. The inflammation in PHN induced COX-2 protein expression that was not affected by low-dose flosulide. COX-1 and COX-2 protein expression was affected by high-dose flosulide, which therefore might lose its selectivity. High-dose flosulide induced a decrease in glomerular prostanoid production possibly because of COX-1 inhibition. Our results suggest that the therapeutic use of flosulide in proteinuria seems advantageous and deserves further studies because the basal prostaglandin levels remain unchanged in the low-dose-treated group, indicating that the compensatory capacity of prostaglandin production, which is essential for the regulation of renal hemodynamics, is maintained.
AB - Background. Nonsteroidal anti-inflammatory drugs (NSAIDs) induce an inhibition of cyclooxygenase (COX), an enzyme that makes prostaglandins. Two isoforms of COX exist: COX-1 represents the constitutively expressed enzyme, whereas COX-2 is the inducible isoform. This study investigated the role of COX-2 in the inflammatory processes of the kidneys of rats with passive Heymann nephritis (PHN), and focused of the effect of a selective COX-2 inhibitor, flosulide. COX-2-selective inhibitors are thought to represent potent anti-inflammatory agents without major renal side effects. Methods. PHN was induced by injecting heterologous Fx1A antiserum into female Wistar rats. Two treatment groups, each consisting of 12 rats with PHN, received either 3 or 9 mg of flosulide/kg body wt/day and were compared with untreated controls. After four weeks, the generation of thromboxane B2 (TxB2) and 6- keto-PGF(1α) were determined in renal tissue and in urine. COX-2 protein expression was investigated by Western blotting using a selective antibody. Results. Rats with PHN exhibited a marked proteinuria of 71 ± 8 mg/24 hr as compared with 2.0 ± 0.3 mg/24 hr in healthy controls (P < 0.01). Treatment with flosulide reduced the proteinuria to 26.1 ± 9 mg/24 hr at 3 mg flosulide/kg body wt/day and 35.5 ± 6 mg/24 hr at 9 mg/kg body wt/day, which was equivalent to a reduction of proteinuria by a maximum of 65% (P < 0.05). This was accompanied by an increase in glomerular TxB2 from 3073 ± 355 to 5255 ± 1041 pg/mg glomerular protein and 6-keto-PGF(1α) from 1702 ± 161 to 2724 ± 770 pg/mg glomerular protein in rats with PHN. COX-2 protein expression was also highly elevated in comparison to healthy controls. Low- dose flosulide treatment had no effect on COX protein expression and renal prostaglandin formation. High-dose flosulide treatment reduced renal prostaglandin production and caused a marked decline in COX-1 and COX-2 protein expression. Urine prostanoid excretion remained unchanged in all therapeutic groups. There was a small though significant reduction in renal creatinine clearance from 0.86 ml ± 0.2/min in untreated controls to 0.6 ml ± 0.1/min in flosulide-treated rats with PHN (P < 0.01) after four weeks. Conclusions. Under the influence of flosulide, a highly COX-2-selective inhibitor, we observed an antiproteinuric drug effect. The inflammation in PHN induced COX-2 protein expression that was not affected by low-dose flosulide. COX-1 and COX-2 protein expression was affected by high-dose flosulide, which therefore might lose its selectivity. High-dose flosulide induced a decrease in glomerular prostanoid production possibly because of COX-1 inhibition. Our results suggest that the therapeutic use of flosulide in proteinuria seems advantageous and deserves further studies because the basal prostaglandin levels remain unchanged in the low-dose-treated group, indicating that the compensatory capacity of prostaglandin production, which is essential for the regulation of renal hemodynamics, is maintained.
KW - Cyclooxygenase
KW - Kidney
KW - NSAIDs
KW - Proteinuria
KW - Renal hemodynamics
KW - Thromboxane A
UR - http://www.scopus.com/inward/record.url?scp=0032731149&partnerID=8YFLogxK
U2 - 10.1046/j.1523-1755.1999.00742.x
DO - 10.1046/j.1523-1755.1999.00742.x
M3 - Article
C2 - 10571785
AN - SCOPUS:0032731149
VL - 56
SP - 1770
EP - 1778
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 5
ER -