Role of vasopressin in regulating renal medullary gene expression

DESCRIPTION (provided by applicant): Diabetes and congestive heart failure are diseases that have been associated with defects in the handling of salt and water by the kidney. Common in individuals with these disorders are elevated circulating levels of vasopressin, the peptide hormone that regulates renal water excretion. Circulating vasopressin plays a critical role in extra-cellular fluid expansion and development of hypertension, thus contributes to the pathogenesis of the disease. Vasopressin has clear long-term actions in the kidney, associated with vasopressin receptor activated processes and transcriptional regulation. Circulating vasopressin also increases the concentrating capacity of the renal medulla by activating the counter current mechanism. The result is an increase in medullary osmotic stress that can directly activate renal cell signaling pathways and gene transcription. Thus specific effects of vasopressin on gene expression are not delineated from secondary alterations associated with this change in medullary osmolality. Preliminary data, from in vivo studies in mice, identifies a role for vasopressin in activating endoplasmic reticulum stress (ER stress) in collecting duct cells. ER stress may be the key to how collecting duct cells survive large increases in medullary osmotic stress during anti-diuresis. Thus we will determine if vasopressin plays a preconditioning role in the medulla to protect collecting duct cells from apoptosis while continuing to upregulate aquaporin-2 expression and increase collecting duct water permeability. We have also identified a novel vasopressin- signaling pathway that decreases the expression of steroid hormone inactivating enzymes in the collecting duct and propose that this vasopressin-mediated pathway may indirectly enhance ENaC expression. Our studies will utilize three complementary model systems, cells, tubule suspensions and animal models to address our central hypothesis that vasopressin promotes AQP2- and ENaC-dependent pathways through direct (V2R) and indirect (osmotic stress) mechanisms. Specific Aims are: 1) To determine if increases in local solute concentrations activate ER stress proteins and protect collecting duct cells from further osmotic stress 2) To determine if vasopressin directly mediates the up-regulation of ER stress proteins via a V2 receptor pathway 3) To determine if vasopressin directly mediates the down-regulation of steroid hormone enzymes via a V2 receptor pathway.