Upregulation of renal and systemic cyclooxygenase-2 in patients with active lupus nephritis.
In lupus nephritis (LN), renal thromboxane A2 (TXA2) production is increased, and inhibition of TXA2 activity improves renal function. In patients with LN, renal function depends very much on vasodilatory prostaglandins, and indeed inhibiting the prostaglandin-forming enzyme cyclooxygenase (COX) with aspirin or related compounds was detrimental on renal hemodynamics in these patients. There are no data so far on whether the excessive TXA2 production in LN derives from upregulation of type I or type II isoforms of COX. It was found that TXB2 synthesis and COX-2 gene expression were higher in peripheral blood mononuclear cells from patients with active LN compared to patients in the inactive form of the disease and to healthy subjects. Unlike COX-2, levels of COX-1 mRNA were comparable in lupus patients and control subjects and were not influenced by the disease activity. Immunoperoxidase studies on kidney biopsies showed COX-1 staining in glomerular arterioles and other renal vessels, with no evident difference between lupus biopsies and control specimens taken from either individuals who were free of renal disease or patients with non-lupus nephropathies. In contrast, COX-2 staining was definitely stronger in specimens from patients with active LN than control specimens. In active LN, COX-2-specific staining was localized mainly in the glomeruli, with a weaker signal on tubuli and in the interstitium. Double-staining studies with an antibody against the macrophage marker CD68 and an anti-COX-2 antibody definitely showed that COX-2 and CD68 often colocalized on the same cell, with only occasional glomerular COX-2-stained mesangial areas. Patients with non-lupus nephropathies had no increase in renal COX-2 expression. These results indicate that COX-2 upregulation is a specific finding of active LN and that monocytes infiltrating the glomeruli contribute to the exaggerated local synthesis of TXA2. If this is correct, COX-2 may soon become a target for therapeutic intervention in this disease.
Tomasoni
S
S
Mario Negri Institute for Pharmacological Research, Ospedali Riuniti di Bergamo Azienda Ospedaliera, Bergamo, Italy.
Noris
M
M
Zappella
S
S
Gotti
E
E
Casiraghi
F
F
Bonazzola
S
S
Benigni
A
A
Remuzzi
G
G
D000328:Adult; D001706:Biopsy; D051546:Cyclooxygenase 2; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000201:enzymology*; D008181:Lupus Nephritis / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000032:analysis; D011863:Radioimmunoassay; D012016:Reference Values; D013256:Steroids / Q000627:therapeutic use; D013928:Thromboxane A2 / Q000378:metabolism*; D015854:Up-Regulation
D007527:Isoenzymes; D008565:Membrane Proteins; D013256:Steroids; D013928:Thromboxane A2; D012313:RNA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D003576:Electron Transport Complex IV