2004 Global Researcher Conference Proceeding

April 09 - 11, 2004

Conference: 2004 Global Researcher Conference
Title: Calcineurin A-alpha knockout is a new model of nephrogenic diabetes insipidus
Authors: Gooch, Jennifer L.; Toro, Juan J.; Guler, Rebecca L.; Barnes, Jeffrey L.
Institutions: Emory University School of Medicine, University of Texas Health Science Center
Gooch Calcineurin is an important signaling molecule in the kidney. Mice that lack Calcineurin A-alpha (CnA-alpha) have impaired kidney function, suffer from failure to thrive, and die approximately 3 weeks post-natal. This study was undertaken to further understand the extent of renal dysfunction as a result of CnA-alpha knockout. CnA-alpha null mice have defective post-natal urine concentrating ability and a corresponding increase in serum osmolality. Aquaporin 2 (AQP2), a key factor in the urine concentrating mechanism, is expressed but is significantly less phosphorylated in CnA-alpha null mice. Accordingly, the urine concentrating response of CnA-alpha null mice to vasopressin is impaired. Consistent with a lack of response to vasopressin and an absence of phosphorylation, AQP2 is not translocated to the apical surface of collecting duct principal cells. Finally, treatment of wildtype animals with cyclosporine A to inhibit calcineurin produces a similar impaired urine concentrating response to vasopressin and alterations in AQP2 phosphorylation and localization, further supporting a role for calcineurin in regulation of AQP2. In conclusion, inhibition of calcineurin results in decreased post-natal urine concentrating ability, a loss of AQP2 phosphorylation, and an impaired response to vasopressin. Our results demonstrate that calcineurin is involved in the regulation of AQP2 by a new mechanism. Furthermore, loss of CnA-alpha represents a previously uncharacterized model of nephrogenic diabetes insipidus.

Calcineurin (CnA) is a molecule that plays an important role in the kidney. Mice that lack calcineurin A-alpha (CnA-alpha) have, among other things, impaired kidney function and die around three weeks after birth. Gooch, et al., studied mice that were missing CnA-alpha and found they could not concentrate urine. They noted that the AQP2 in these mice was significantly less phosphorylated (i.e., it did not have the phosphorus groups attached where healthy AQP2 does). This under-phosphorylated AQP2 cannot travel to its work site, the cell membrane. When the researchers treated normal mice with a chemical that inhibits CnA-alpha, these mice exhibited the same lack of urine concentrating ability, the AQP2 was under-phosphorylated and could not reach the cell membrane.

The researchers’ work indicates that calcineurin plays an important role in AQP2’s ability to function properly and that loss of CnA-alpha can result in NDI.