Renal medullary interstitial COX-2 is essential in preventing salt-sensitve hypertension and maintaining renal inner medulla/papilla structural integrity

Cyclooxygenase (COX)-derived prostaglandins regulate renal hemodynamics and salt and water homeostasis. Inhibition of COX activity causes blood pressure elevation. In addition, chronic analgesic abuse can induce renal injury, including papillary necrosis. COX-2 is highly expressed in the kidney papilla in renal medullary interstitial cell (RMICs). However, its role in blood pressure and papillary integrity in vivo has not been definitively studied. In mice with selective, inducible RMIC COX-2 deletion, a high salt diet led to an increase in blood pressure that peaked at 4–5 weeks and was associated with increased papillary expression of aquaporin 2 and epithelial sodium channel and decreased expression of cystic fibrosis transmembrane conductance regulator. With continued high salt feeding, the mice with RMIC COX-2 deletion had progressive decreases in blood pressure from its peak. After return to a normal salt diet for 3 weeks, blood pressure remained low and was associated with a persistent urinary concentrating defect. Within two weeks of institution of a high salt diet, increased apoptotic RMICs and collecting duct cells could be detected in papillae with RMIC deletion of COX-2, and by 9 weeks of high salt, there was a striking loss of the papillae. Therefore, renal medullary interstitial cell COX-2 expression plays a crucial role in renal handling water and sodium homeostasis, preventing salt-sensitive hypertension, and maintaining structural integrity of papilla.