Upregulation of cyclooxygenase-1 and the PGE2 receptor EP2 in rat and human mesangioproliferative glomerulonephritis.
OBJECTIVE
Glomerular expression and localization of the two cyclooxygenase isoforms, Cox-1 and Cox-2, and the prostaglandin E2 receptor EP2 were investigated in a rat model of transient mesangioproliferative glomerulonephritis. Cox expression was also studied in biopsies from patients with IgA nephropathy.


METHODS
After induction of glomerulonephritis by i.v. injection of a monoclonal anti-Thy1.1 antibody, rats were sacrificed at day 2, 6, 12 and 56. Changes in protein expression were detected by immunohistochemistry. Glomerular mRNA levels were analyzed by real time polymerase chain reaction (PCR).


RESULTS
In normal rat kidney, immunoreactivity of Cox-1 was detected predominantly in collecting duct cells and that of Cox-2 in the macula densa. Cox-1 staining showed a massive transient increase in diseased glomeruli at day 6, localized mainly to mesangial cells coinciding with cell proliferation, which also peaked at day 6. Upregulation of Cox-1 was also evident at the mRNA level (4 fold). Cox-2 expression in the macula densa region transiently increased at day 6, but no significant upregulation of Cox-2 was observed in glomerular cells at any time point. Prostaglandin E2 receptor EP2 mRNA and protein were detected in rat glomeruli. EP2 immunoreactivity was prominent on podocytes in normal rats while at day 6 of the disease also mesangial cells stained positive. In biopsies of patients with IgA nephritis, predominant expression of Cox-1, but not Cox-2, was found in glomeruli, whereas Cox-2 was strongly expressed in infiltrating interstitial cells.


CONCLUSIONS
The upregulation of glomerular Cox-1 but not Cox-2 and the parallel induction of the EP-2 receptor, which was shown to mediate cAMP accumulation in mesangial cells, suggest that induction of prostaglandin formation may contribute to the resolution rather than to the progression of anti-Thy1.1 nephritis. The expression pattern of Cox-1 and Cox-2 in human IgA nephritis points to a role for both Cox isoforms in human glomerular inflammation.
Hartner
A
A
Medizinische Klinik IV, Universität Erlangen-Nürnberg, Erlangen, Germany.
Pahl
A
A
Brune
K
K
Goppelt-Struebe
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D005920:Glomerular Mesangium / Q000201:enzymology; D015432:Glomerulonephritis, Membranoproliferative / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007527:Isoenzymes / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000737:chemistry; D007678:Kidney Glomerulus / Q000737:chemistry / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000032:analysis / Q000235:genetics*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D018800:Thy-1 Antigens / Q000276:immunology; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D007527:Isoenzymes; D008565:Membrane Proteins; C545644:PTGER2 protein, human; C545646:Ptger2 protein, rat; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D018800:Thy-1 Antigens; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat