Summary (Pro)renin receptor (PRR), a new member of the renin-angiotensin system (RAS), has emerged as a key regulator of renal handling of Na+ and water, and blood pressure (BP). Renal action of PRR is at least in part mediated through its ability to activate tissue prorenin and renin. In preliminary studies, investigation of a “non-specific” protein band recognized by a custom-made anti-PRR antibody has led to identification of a novel 24-kDa isoform of PRR, termed as PRR24. PRR24 was encoded by a novel cDNA with part of 5’UTR arising from retention of intron 3 and an ATG in exon 5 as an alternative start codon so that this isoform overlaps completely with PRR except that N-terminal 136 amino acids are missing. PRR24 expression was predominantly detected in the renal medulla. PRR24 selectively bound and activated renin but not prorenin whereas PRR non-selectively interacted both prorenin and renin. In cultured collecting duct (CD) cells, PRR24 translocated from the cytosol to the nucleus in a cAMP/PKA-dependent manner following vasopressin (AVP) treatment. The trafficking event also occurred in mouse renal medulla following water deprivation. PRR24 was not only required but also sufficient for induction of aquaporin-2 (AQP2) transcription induced by AVP. Furthermore, ablation of PRR24 by mutagenesis of its start codon in mice (termed PRR24mut) induced nephrogenic diabetes insipidus (NDI) associated with volume contraction and hypotension as well as reduced renal medullary renin activity. Therefore, we hypothesize that PRR24 serves as a specific renin receptor critically involved in AVP-induced signaling pathway to control AQP2 transcription and thus urine concentrating capability and plasma volume (Fig. 1). To test this hypothesis, we will conduct a full panel of phenotypical analysis of PRR24mut mice during perturbation of water balance. In addition, we will define the transcriptional activity of PRR24 in regulation of AQP2 expression through analysis of the threonine/threonine sites of PKA-dependent phosphorylation of PRR24 and fine mapping of PRR24- responsive elements in AQP2 promoter during AVP treatment. Overall, this proposal is expected to offer novel insight into the function of a newly described PRR24 in the kidney.