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

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

Acta physiologica (Oxford, England) (2022-05-12)
Signe S Tofteng, Line Nilsson, Amalie K Mogensen, Rikke Nørregaard, Rolf Nüsing, Mikhail Diatchikhine, Lars Lund, Claus Bistrup, Boye L Jensen, Kirsten Madsen
ABSTRACT

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. 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, PGE2 , and thromboxane were determined in human tissue. 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, PGE2 -, and prostacyclin synthases, and prostacyclin and thromboxane receptor mRNAs, (iii) increased mRNA and protein of PGE2 -EP2 receptor level but unchanged PGE2 tissue concentration, and (iv) two- to threefold increased thromboxane synthase mRNA and protein levels, and increased thromboxane B2 tissue concentration in cortex and outer medulla. COX-2 protects in the early phase against obstruction-induced fibrosis and maintains angiogenic factors. Increased PGE2 -EP2 receptor in obstructed human and murine kidneys could contribute to protection.

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DAPI, for nucleic acid staining