Selective Cyclooxygenase-2 Inhibition Upregulates Renal Cortical α&lt;sub&gt;v&lt;/sub&gt; Integrin Expression

In vivo imaging of a v b 3 expression has important diagnostic and therapeutic applications. Multimeric cyclic RGD peptides are capable of improving the integrin a v b 3 -binding affinity due to the polyvalency effect. Here we report an example of 18 F-labeled tetrameric RGD peptide for PET of a v b 3 expression in both xenograft and spontaneous tumor models. Methods: The tetrameric RGD peptide EfE[c(RGDyK)] 2 g 2 was derived with amino-3,6,9-trioxaundecanoic acid (mini-PEG; PEG is poly(ethylene glycol)) linker through the glutamate a-amino group. NH 2 -mini-PEG-EfE[c(RGDyK)] 2 g 2 (PRGD4) was labeled with 18 F via the N-succinimidyl-4-18 F-fluorobenzoate ( 18 F-SFB) prosthetic group. The receptor-binding characteristics of the tetrameric RGD peptide tracer 18 F-FPRGD4 were evaluated in vitro by a cell-binding assay and in vivo by quantitative microPET imaging studies. Results: The decay-corrected radiochemical yield for 18 F-FPRGD4 was about 15%, with a total reaction time of 180 min starting from 18 F-F 2 . The PEGylation had minimal effect on integrin-binding affinity of the RGD peptide. 18 F-FPRGD4 has significantly higher tumor uptake compared with monomeric and dimeric RGD peptide tracer analogs. The receptor specificity of 18 F-FPRGD4 in vivo was confirmed by effective blocking of the uptake in both tumors and normal organs or tissues with excess c(RGDyK). Conclusion: The tetrameric RGD peptide tracer 18 F-FPRGD4 possessing high integrin-binding affinity and favorable biokinetics is a promising tracer for PET of integrin a v b 3 expression in cancer and other angiogenesis related diseases.

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“…Whether the higher renal uptake and retention of 18 F-FPRGD4 is integrin a v b 3 -mediated is yet to be tested (36).…”

Section: Discussionmentioning

confidence: 99%

microPET of Tumor Integrin v 3 Expression Using 18F-Labeled PEGylated Tetrameric RGD Peptide (18F-FPRGD4)

Wu¹,

Li²,

Chen³

et al. 2007

Journal of Nuclear Medicine

194

275

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“…This observation agrees with the in vivo finding that COX-2 inhibition reduced renal PGE 2 formation but in parallel enhanced renal a v integrin expression in rats with passive Heyman nephritis. 3 ''Prostaglandin E 2 alone reduced physiological a v integrin mRNA expression in cultured mesangial cells''…”

Section: Discussionmentioning

confidence: 99%

“…This mechanism can explain the previous finding that celecoxib upregulates renal cortical a v integrin expression in experimental nephritis. 3 …”

Section: Discussionmentioning

confidence: 99%

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COX-2 dependent PGE₂downregulates α_vintegrin expression via the EP₃receptor in cultured mesangial cells

Waldner

Schrör²,

Heering³

2004

J Clin Pathol

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Background: In experimental glomerulonephritis, inhibition of cyclooxygenase 2 (COX-2) enhances the renocortical expression of pathogenic a v integrins. Aims: To study whether this effect is mediated by prostaglandin E 2 (PGE 2 ) acting through its EP 3 receptor in cultured rat mesangial cells (MCs). Methods: MCs were incubated with lipopolysaccharide (LPS), celecoxib, PGE 2 , or the selective EP 3 agonist, MB28767. The expression of COX-2, EP 3 , and a v integrin mRNA was measured by reverse transcriptase polymerase chain reaction. Results: LPS upregulated COX-2 expression 2.8-fold and a v integrin expression twofold. The COX-2 inhibitor celecoxib increased a v integrin mRNA expression twofold. Both exogenous PGE 2 and the specific EP 3 receptor agonist, MB28767, reduced constitutive a v integrin mRNA expression to half normal values. COX-2 dependent PGE 2 suppressed the expression of a v integrin mRNA mediated by the EP 3 receptor in MCs. Conclusions: These results suggest that COX-2 suppresses the expression of a v integrins by an increased production of PGE 2 activating its EP 3 receptor in glomerulonephritis.

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“…Previous investigations have shown enhanced COX-2 expression in rats with passive Heymann nephritis (PHN), a model for human membranous glomerulonephritis [1, 10, 11]. COX-2-selective inhibition was shown to lead to reduced proteinuria, but a total suppression of COX-2 and COX-2-dependent prostaglandins was associated with decreased renal function [1].…”

Section: Introductionmentioning

confidence: 99%

Different Effect of Cyclosporine A and Mycophenolate Mofetil on Passive Heymann Nephritis in the Rat

Blume

Heise

Hess

et al. 2005

Nephron Exp Nephrol

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Background: While cyclosporine A (CsA) is an effective therapy for nephrotic syndrome, it has nephrotoxic side effects. We compared the anti-proteinuric effects and nephrotoxicity in rats with passive Heymann nephritis (PHN) of CsA and mycophenolate mofetil (MMF). Methods: PHN was induced in female Wistar rats. Two treatment groups consisting of 8 rats each received either 25 mg of CsA or 25 mg of MMF/kg body weight/day and were compared with untreated controls. Kidney function and proteinuria were monitored over 4 weeks. Western blots were used for densitometric analysis of renal cyclooxygenase-2 (COX-2) protein expression. Thromboxane B₂ (TxB₂) and 6-keto-PGF_1α were determined by radioimmunoassays (RIAs) in renal tissue and urine. Results: Rats with PHN exhibited a marked proteinuria of 12.76 ± 4.42 vs. 0.73 ± 0.28 mg/24 h (p < 0.01) and showed increased glomerular concentrations of TxB₂ and 6-keto-PGF_1α (992.6 ± 216.9 and 1,187.0 ± 54.2 pg/mg protein, respectively) compared with healthy controls (595 ± 196.17 and 729 ± 297.84, respectively) and a strongly induced COX-2 protein expression. CsA and MMF treatment reduced PHN-related proteinuria to 2.10 ± 1.47 and 1.47 ± 7.2 mg/24 h, respectively. In rats with PHN, CsA induced a significant deterioration of renal function and enhanced urine excretion of thromboxane A₂, paralleled by a significant, twofold increase in COX-2 protein expression and renal prostaglandins. By contrast, MMF treatment in rats with PHN was not nephrotoxic and had no effect on prostaglandin production. COX-2 protein expression under MMF was suppressed. Conclusion: While the antiproteinuric efficacy of MMF and CsA in PHN was comparable, the absence of nephrotoxicity might favor MMF in the treatment of nephrotic syndrome. The CsA-induced increase in COX-2 expression and COX-2-dependent prostacyclin may indicate a mechanism that compensates nephrotoxicity in the diseased and CsA-exposed kidney.

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Selective Cyclooxygenase-2 Inhibition Upregulates Renal Cortical α<sub>v</sub> Integrin Expression

Cited by 5 publications

References 39 publications

microPET of Tumor Integrin v 3 Expression Using 18F-Labeled PEGylated Tetrameric RGD Peptide (18F-FPRGD4)

microPET of Tumor Integrin v 3 Expression Using 18F-Labeled PEGylated Tetrameric RGD Peptide (18F-FPRGD4)

COX-2 dependent PGE₂downregulates α_vintegrin expression via the EP₃receptor in cultured mesangial cells

Different Effect of Cyclosporine A and Mycophenolate Mofetil on Passive Heymann Nephritis in the Rat

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Selective Cyclooxygenase-2 Inhibition Upregulates Renal Cortical α<sub>v</sub> Integrin Expression

Cited by 5 publications

References 39 publications

microPET of Tumor Integrin v 3 Expression Using 18F-Labeled PEGylated Tetrameric RGD Peptide (18F-FPRGD4)

microPET of Tumor Integrin v 3 Expression Using 18F-Labeled PEGylated Tetrameric RGD Peptide (18F-FPRGD4)

COX-2 dependent PGE2downregulates αvintegrin expression via the EP3receptor in cultured mesangial cells

Different Effect of Cyclosporine A and Mycophenolate Mofetil on Passive Heymann Nephritis in the Rat

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COX-2 dependent PGE₂downregulates α_vintegrin expression via the EP₃receptor in cultured mesangial cells