Increased expression of cyclooxygenase-1 and -2 in the diabetic rat renal medulla.
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.
Nasrallah
Rania
R
Dept. of Cellular and Molecular Medicine, and Kidney Research Centre, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Rm. 1337, Ottawa, Ontario, Canada K1H 8M5.
Landry
Anne
A
Singh
Sonia
S
Sklepowicz
Monika
M
Hébert
Richard L
RL
D000818:Animals; D015152:Blotting, Northern; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D015232:Dinoprostone / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000494:pharmacology; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D007679:Kidney Medulla / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype
D007527:Isoenzymes; D008565:Membrane Proteins; C545637:Ptger1 protein, rat; C545652:Ptger4 protein, rat; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D005947:Glucose; D015232:Dinoprostone