The kidneys exhibit a high capacity for prostaglandin synthesis through cyclooxygenase (COX) enzymes. COX-1 is stably expressed at levels ~20–30 times higher in medulla compared to cortex. COX-2 expression is equally distributed and strongly regulated by NaCl balance. In kidney cortex, COX-2 in thick ascending limb of Henle's loop is stimulated significantly in conditions with a negative NaCl balance e.g. diuretic treatment, renal artery stenosis or angiotensin converting enzyme inhibition. COX-2 activity supports renin release from the JG- cells in the afferent arteriole through PGE ₂ and PGI ₂. A 5% hypo-osmotic challenge of isolated JG-cells stimulates renin release dependent on aquaporin-1 and COX-2 activity through cAMP. This cascade could be relevant in situation with low or inhibited NaCl transport across the macula densa. In kidney medulla, COX- 2 expression is significantly stimulated by water deprivation or dietary NaCl loading. COX-2 is expressed in vasa recta in human kidney and in the interstitial cells in rodent kidney. Dietary NaCl loading with systemic or local inhibition of COX-2 in the kidney medulla precipitates hypertension and suppresses medullary blood flow. Our recent data from systemic arteries show that PGE ₂ supports blood flow by stimulation of eNOS activity and cGMP formation. A similar mechanism could be relevant in the kidney medulla. In conclusion, the renal COX- prostaglandin cascade is oppositely regulated in cortex and medulla by NaCl balance. In cortex, COX-2 activity is increased and supports GFR, RBF and renin release in NaCl depleted states. In medulla, COX-2 activity supports medullary blood flow, cell survival and NaCl excretion in NaCl loaded states and thereby lowers blood pressure.