V2 receptor activation induces renal medullary cell proliferation in mice with a reduced urinary concentrating ability

Abstract

Increases in circulating vasopressin trigger receptor activated pathways in the kidney and increase the renal concentrating capacity of the medulla. The renal medulla encounters an increase in osmotic stress following increases in vasopressin. Mice which lack the AQP1 gene fail to generate a hypertonic medullary interstitium thus have a urinary concentrating defect. This study used AQP1 null mice as a tool to determine the specific effects of vasopressin on medullary gene expression, in the absence of high osmotic stress. We infused dDAVP, a V2 receptor agonist, into AQP1 null mice for 7 days. Growth regulated genes cyclin D1, early growth response gene 1 and activated transcription factor 3 (ATF3) mRNA were significantly increased in the medulla of AQP1 null mice following dDAVP infusion. Western blot analysis confirmed the increase in cyclin D1 protein (dDAVP infused 161±9% v 100±6% AQP1 null controls, p<0.05) and ATF3 (dDAVP infused 461±49% v 100±19% AQP1 null controls, p<0.05). Using a proliferating cell nuclear antigen (PCNA) antibody we determined that dDAVP increased renal medullary cell proliferation in AQP1 null mice. AQP2 and PCNA dual labeling was performed; proliferating cells were positive for AQP2. dDAVP did not increase proliferation in normal mice. We conclude that dDAVP infusion induces renal medullary collecting duct cell proliferation in mice with a decreased urinary concentrating ability.