| First Author | Gilbert ML | Year | 2015 |
| Journal | Am J Physiol Renal Physiol | Volume | 308 |
| Issue | 6 | Pages | F627-38 |
| PubMed ID | 25587115 | Mgi Jnum | J:235112 |
| Mgi Id | MGI:5792792 | Doi | 10.1152/ajprenal.00222.2014 |
| Citation | Gilbert ML, et al. (2015) Expression of a dominant negative PKA mutation in the kidney elicits a diabetes insipidus phenotype. Am J Physiol Renal Physiol 308(6):F627-38 |
| abstractText | PKA plays a critical role in water excretion through regulation of the production and action of the antidiuretic hormone arginine vasopressin (AVP). The AVP prohormone is produced in the hypothalamus, where its transcription is regulated by cAMP. Once released into the circulation, AVP stimulates antidiuresis through activation of vasopressin 2 receptors in renal principal cells. Vasopressin 2 receptor activation increases cAMP and activates PKA, which, in turn, phosphorylates aquaporin (AQP)2, triggering apical membrane accumulation, increased collecting duct permeability, and water reabsorption. We used single-minded homolog 1 (Sim1)-Cre recombinase-mediated expression of a dominant negative PKA regulatory subunit (RIalphaB) to disrupt kinase activity in vivo and assess the role of PKA in fluid homeostasis. RIalphaB expression gave rise to marked polydipsia and polyuria; however, neither hypothalamic Avp mRNA expression nor urinary AVP levels were attenuated, indicating a primary physiological effect on the kidney. RIalphaB mice displayed a marked deficit in urinary concentrating ability and greatly reduced levels of AQP2 and phospho-AQP2. Dehydration induced Aqp2 mRNA in the kidney of both control and RIalphaB-expressing mice, but AQP2 protein levels were still reduced in RIalphaB-expressing mutants, and mice were unable to fully concentrate their urine and conserve water. We conclude that partial PKA inhibition in the kidney leads to posttranslational effects that reduce AQP2 protein levels and interfere with apical membrane localization. These findings demonstrate a distinct physiological role for PKA signaling in both short- and long-term regulation of AQP2 and characterize a novel mouse model of diabetes insipidus. |
