Renal prostaglandins (PG), renin, and cortisol are necessary for normal kidney development and function during fetal life. We examined the effects of cortisol infusion before completion of nephrogenesis (d 109 -116 gestation; 2.0 -3.0 mg hydrocortisone succinate/24 h) on the renal mRNA expression of PGHS-2, the PGE 2 receptors, EP 2 and EP 4 , and renin in fetal sheep. Cortisol infusion raised plasma cortisol levels to 42.8 Ϯ 6.0 nmol/L compared with saline infusion levels of 1.5 Ϯ 0.5 nmol/L (p Ͻ 0.001), but had no effect on fetal body weight, proportional kidney mass, or blood gases. Cortisol decreased significantly the relative expression of renin mRNA (saline: 0.93 Ϯ 0.06 units; cortisol: 0.32 Ϯ 0.03 units, p Ͻ 0.05), however it had no effect upon the expression of PGHS-2, EP 2 , or EP 4 mRNA in fetal sheep kidney. Although there is substantial evidence that PGE 2 acting through either the EP 2 or EP 4 receptor stimulates renin synthesis in the adult kidney, our results have demonstrated that before the completion of nephrogenesis, cortisol down-regulation of renin mRNA expression is independent of any change in the expression of PGHS-2, EP 2 , or EP 4 mRNA expression. During nephrogenesis, the insensitivity of PGHS-2, EP 2 , and EP 4 expression to down-regulation by cortisol may permit continued PG regulation of renal development and urine formation. The first budding of the fetal sheep metanephric kidney begins between gestational d 27 and 30, and by d 41 it contains renin, angiotensinogen, and angiotensinogen converting enzyme and is producing urine (1). Nephrogenesis is completed by d 130, more than 2 wk before birth at 145-150 d (2). PG and the RAS are both endogenous factors responsible for renal development in fetal life, however, cortisol, which is present from early in fetal life and is necessary for many developmental aspects of the lung, gut, and other organs, has an uncertain role in the development or function of the fetal kidney (3).Prostaglandin E 2 , synthesized by either isoform of PG endoperoxide G/H synthase (PGHS-1 or -2), is the primary PG produced by the fetal sheep kidney during late gestation (4). Through interactions with the EP 1-4 receptor subtypes (5), PGE 2 regulates renal function and has been demonstrated to be essential for normal nephrogenesis (6). Renal PGE 2 also promotes the synthesis and secretion of renin (7). It is clear from several studies that the RAS also plays an important role in renal development and function in the fetus (8, 9). Although bilateral adrenalectomy has no apparent effect on fetal renal function until d 142 of gestation because of placental-maternal exchange mechanisms that maintain fetal electrolyte and fluid balance (3), infusion of cortisol increases allantoic fluid volume at 64 d (10) and may mature the fetal kidney (11), whereas acute administration of cortisol to the immature fetal sheep kidney (at 114 d) leads to natriuresis and diuresis (12). These data suggest that cortisol has an effect on fetal kidney function or maturation. The relationsh...