Fibroblast Cyclooxygenase 2 Expression in the Development of Progressive Kidney Fibrosis

Cyclooxygenase 2 expression increased in kidney fibroblasts in response to a fibrotic stimulus. Fibroblast cyclooxygenase 2-mediated PGE2 promoted an anti-inflammatory, proreparative phenotype in macrophages by activating the PGE2 receptor EP4. Selective deletion of fibroblast cyclooxygenase 2 promoted a proinflammatory macrophage phenotype, which exacerbated kidney fibrosis.

During progressive kidney injury, pericytes and resident fibroblasts migrate, proliferate, and differentiate into myofibroblasts, which are the major source of extracellular matrix deposition. Both interstitial fibroblasts and macrophages contribute to kidney fibrosis and coexist within the fibrotic niche. However, the potential interaction between fibroblasts and macrophages and its role in kidney fibrosis remains incompletely understood. Previous studies have indicated a role for kidney prostaglandins to limit fibroblast activity and myofibroblast transformation.

Inducible PDGFR β -Cre mice were crossed to the indicated floxed mice to selectively delete either cyclooxygenase 2 (COX-2) or the PGE2 receptors EP2 and EP4. Unilateral ureteral obstruction was used as a model of progressive kidney fibrosis.

Selective deletion of cyclooxygenase-2 expression in fibroblasts (FibCOX-2-/-) increased kidney fibrosis in association with kidney macrophages with a proinflammatory and profibrotic phenotype. The highest differentially expressed gene in these macrophages was the profibrotic factor SPP1/osteopontin, and deletion of kidney macrophages with clodronate inhibited kidney expression of SPP1 and ameliorated fibrosis in FibCOX2-/- mice.

Our findings suggest that fibroblast COX-2 protects against progressive kidney fibrosis, potentially through a regulatory interplay that modulates the surrounding macrophage phenotype during chronic kidney injury.