Cyclooxygenase-2 Modulation in Renal Pathophysiology

Cyclooxygenase-2 (COX-2) is a key inducible enzyme in the renal prostanoid biosynthesis pathway, converting arachidonic acid into prostaglandin H2, the precursor to various prostaglandins central to renal haemodynamics, inflammation and cellular adaptation. Under physiological conditions, COX-2 expression is low in the kidney but is upregulated in response to hypoxia, hyperglycaemia, oxidative stress and hormonal stimuli. Enhanced COX-2 activity drives increased production of prostaglandin E2 (PGE2) which modulates glomerular filtration, tubular transport and vascular tone. However, persistent COX-2 induction contributes to maladaptive processes including glomerulosclerosis, tubulointerstitial fibrosis and acute tubular injury. Therapeutic modulation of COX-2, either through selective inhibition or downstream receptor targeting, has emerged as a nuanced strategy to balance beneficial prostanoid signalling against deleterious inflammation and fibrotic progression in both acute and chronic kidney disease.

Research from Nature Portfolio

Recent studies have demonstrated that inhibition of the prostaglandin E2 receptor subtype EP4 attenuates progression of both diabetic and non-diabetic chronic kidney disease through mechanisms distinct from classic COX-2 blockade. In rodent models, EP4 antagonism reduced albuminuria and glomerular scarring without affecting blood pressure or hyperfiltration, and prevented TGF-β1-induced podocyte dedifferentiation in vitro. These findings suggest that selective targeting of downstream prostanoid receptors may provide renoprotection with fewer haemodynamic side effects than non-selective COX inhibition.

Cyclooxygenase-2 Modulation in Renal Pathophysiology publication trend

The graph below shows the total number of articles in cyclooxygenase-2 modulation in renal pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Cyclooxygenase-2 (COX-2): An inducible enzyme that converts arachidonic acid into prostaglandin precursors under inflammatory or stress conditions in the kidney.

Prostaglandin E2 (PGE2): A bioactive lipid mediator produced by COX-2 that signals through membrane-bound E-prostanoid receptors to regulate renal haemodynamics and cell function.

Prostaglandin transporter (PGT): A membrane protein that mediates cellular uptake of extracellular prostaglandins, affecting intracellular prostanoid levels.

Dipeptidyl peptidase-4 (DPP-4): A serine protease involved in peptide cleavage and regulation of inflammatory responses, shown to interact with prostaglandin pathways in tubular cells.

E-prostanoid receptor EP2: A G protein-coupled receptor subtype for PGE2 whose activation modulates cyclic AMP signalling and can attenuate fibrotic responses in renal tissue.

Epithelial-mesenchymal transition (EMT): A process by which epithelial cells acquire mesenchymal characteristics, contributing to renal fibrosis in chronic kidney disease.

References

1. Prostaglandin Transporter and Dipeptidyl Peptidase-4 as New Pharmacological Targets in the Prevention of Acute Kidney Injury in Diabetes: An In Vitro Study. International Journal of Molecular Sciences (2024).
2. Activation of the prostaglandin E2 EP2 receptor attenuates renal fibrosis in unilateral ureteral obstructed mice and human kidney slices. Acta Physiologica (2019).
3. EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease. Scientific Reports (2017).