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Increased expression of cyclooxygenase-1 and -2 in the diabetic rat renal medulla

Department of Cellular and Molecular Medicine and Kidney Research Centre, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5

Submitted 19 December 2002 ; accepted in final form 24 July 2003

Alterations in renal prostaglandins (PGs) may contribute to some of the renal manifestations in diabetes leading to nephropathy. PG production is dependent on the activity of cyclooxygenases (COX-1 AND -2) and PG synthases. Our present study investigated levels of these enzymes in streptozotocin-diabetic rats at 2, 4, 6, and 8 wk of diabetes. Immunohistochemical analysis revealed an increase in COX signal in the inner and outer medulla of diabetic rats. This was confirmed by Western blotting, showing up to a fourfold increase in both COX isoforms at 4–6 wk of diabetes. Also, Western blot analysis revealed a sixfold increase in PGE₂ synthase expression in the outer medullary region of 6-wk diabetic rats but no difference in the inner medulla. In cultured rat inner medullary collecting duct (IMCD), levels of COX were increased two- to threefold in cells exposed for 4 days to 37.5 mM glucose compared with control of 17.5 mM. While no change in PGE₂ synthase levels was noted, PGE₂ synthesis was increased. Furthermore, levels of EP₁ and EP₄ mRNA were increased, as well as a twofold increase in EP₄ protein levels. Future studies will determine which COX isoform is contributing to the majority of PGE₂ produced in the diabetic IMCD and the significance of these findings to disturbances in IMCD function and to the progression of diabetic nephropathy.

prostaglandin E₂; streptozotocin-diabetic rats; inner medullary collecting duct; EP₄ receptor

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