AQP1 null mice have a defect in the renal concentrating gradient due to their inability to generate a hyperosmotic medullary interstitium. To determine the effect vasopressin on renal medullary gene expression, in the absence of high local osmolarity, we infused dDAVP, a V2 receptor specific agonist, into AQP1 null mice for 7 days. cDNA microarray analysis was performed on the renal medullary tissue and 5140 genes of the possible 12,000 genes on the array were included in the analysis. In the renal medulla of AQP1 null mice 245 transcripts were identified as increased by dDAVP infusion and 200 transcripts as decreased (1.5-fold or more). Quantitative real-time PCR measurements confirmed the increases seen for cyclin D1, Egr-1 and ATF3; genes associated with changes in cell cycle/growth. Changes in mRNA expression were correlated with changes in protein expression by semi-quantitative immunoblotting; cyclin D1 and ATF3 were significantly increased in abundance following dDAVP infusion in the renal medulla of AQP1 null mice (161% and 461% respectively). A significant increase in proliferation of medullary collecting ducts cells, following V2R activation, was identified by PCNA immunohistochemistry; co-localization studies with AQP2 indicated that the increase in proliferation was primarily observed in principal cells of the inner medullary collecting duct (IMCD). V2R activation, via dDAVP, increased AQP2 and AQP3 protein abundance in the cortical collecting ducts of AQP1 null mice. However, V2R activation did not increase AQP2 protein abundance in the IMCD of AQP1 null mice.