Calcineurin (Cn)-Aalpha-deficient mice develop abnormalities of postnatal kidney development, similar to that of cyclooxygenase (COX)-2-deficient mice. The present study was undertaken to examine expression and regulation of Cn isoforms in the developing kidney during the postnatal period and further characterize the relationship between Cn and COX-2. The protein expressions of all three Cn isoforms, including Cn-Aalpha, -Abeta, and -B, as determined by immunoblotting, increased in parallel in the first postnatal week and declined gradually with age. Renal Cn-Aalpha and -Abeta mRNA expressions were both developmentally regulated in the same fashion as their protein expressions, whereas renal Cn-B1 mRNA was not obviously induced in the first postnatal week. Immunohistochemistry demonstrated colocalization of Cn-Aalpha, Cn-Abeta, and COX-2 in the same cells of thick ascending limb and macula densa. Administration with cyclosporine A (2.5 mg.kg(-1).day(-1)) during the postnatal period remarkably suppressed renal COX-2 expression as assessed by both immunoblotting and immunohistochemistry. Deletion of Cn-Aalpha but not Cn-Abeta in mice significantly reduced renal COX-2 expression at the postnatal period. Together, these data suggest that renal Cn isoforms are subject to normal developmental regulation and they may play a role in postnatal kidney development via interaction with COX-2.