Increased COX-2 after ureter obstruction attenuates fibrosis and is associated with EP2 receptor upregulation in mouse and human kidney

Aim Cyclooxygenase-2 (COX-2) activity protects against oxidative stress and apoptosis early in experimental kidney injury. The present study was designed to test the hypothesis that COX-2 activity attenuates fibrosis and preserves microvasculature in injured kidney. The murine unilateral ureteral-obstruction (UUO) model of kidney fibrosis was employed and compared with human nephrectomy tissue with and without chronic hydronephrosis. Methods Fibrosis and angiogenic markers were quantified in kidney tissue from wild-type and COX-2(-/-) mice subjected to UUO for 7 days and in human kidney tissue. COX-enzymes, prostaglandin (PG) synthases, PG receptors, PGE(2), and thromboxane were determined in human tissue. Results COX-2 immunosignal was observed in interstitial fibroblasts at baseline and after UUO. Fibronectin, collagen I, III, alpha-smooth muscle actin, and fibroblast specific protein-1 mRNAs increased significantly more after UUO in COX-2(-/-) vs wild-type mice. In vitro, fibroblasts from COX-2(-/-) kidneys showed higher matrix synthesis. Compared to control, human hydronephrotic kidneys showed (i) fibrosis, (ii) no significant changes in COX-2, COX-1, PGE(2)-, and prostacyclin synthases, and prostacyclin and thromboxane receptor mRNAs, (iii) increased mRNA and protein of PGE(2)-EP2 receptor level but unchanged PGE(2) tissue concentration, and (iv) two- to threefold increased thromboxane synthase mRNA and protein levels, and increased thromboxane B-2 tissue concentration in cortex and outer medulla. Conclusion COX-2 protects in the early phase against obstruction-induced fibrosis and maintains angiogenic factors. Increased PGE(2)-EP2 receptor in obstructed human and murine kidneys could contribute to protection.

Automated summary

COX-2 activity protects against fibrosis and preserves microvasculature in injured kidney. In the study, it was found that fibrosis markers increased significantly in COX-2(-/-) mice and human kidney tissue with obstruction-induced kidney disease. Fibroblasts from COX-2(-/-) kidneys also showed increased matrix synthesis. Additionally, obstructed human kidneys showed increased PGE2-EP2 receptor levels, which could contribute to protection.