Upregulation of cyclooxygenase-1 and the PGE(2) receptor EP2 in rat and human mesangioproliferative glomerulonephritis

Objective and Design: Glomerular expression and localization of the two cyc looxygenase isoforms, Cox-1 and Cox-2, and the prostaglandin E2 receptor EP 2 were investigated in a rat model of transient mesangioproliferative glome rulonephritis. Cox expression was also studied in biopsies from patients wi th IgA nephropathy. Materials and Treatment: After induction of glomerulonephritis by i.v. inje ction of a monoclonal anti-Thy1.1 antibody, rats were sacrificed at day 2, 6, 12 and 56. Changes in protein expression were detected by immunohistoche mistry. Glomerular mRNA levels were analyzed by real time polymerase chain reaction (PCR). Results: In normal rat kidney, immunoreactivity of Cox-1 was detected predo minantly in collecting duct cells and that of Cox-2 in the macula densa. Co x-1 staining showed a massive transient increase in diseased glomeruli at d ay 6, localized mainly to mesangial cells coinciding with cell proliferatio n, which also peaked at day 6. Upregulation of Cox-1 was also evident at th e mRNA level (4 fold). Cox-2 expression in the macula densa region transien tly increased at day 6, but no significant upregulation of Cox-2 was observ ed in glomerular cells at any time point. Prostaglandin E2 receptor EP2 mRN A and protein were detected in rat glomeruli. EP2 immunoreactivity was prom inent on podocytes in normal rats while at day 6 of the disease also mesang ial cells stained positive. In biopsies of patients with IgA nephritis, pre dominant expression of Cox-1, but not Cox-2, was found in glomeruli, wherea s Cox-2 was strongly expressed in infiltrating interstitial cells. Conclusions: The upregulation of glomerular Cox-1 but not Cox-2 and the par allel induction of the EP-2 receptor, which was shown to mediate cAMP accum ulation in mesangial cells, suggest that induction of prostaglandin formati on 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 ne phritis points to a role for both Cox isoforms in human glomerular inflamma tion.