Role of cAMP-Phosphodiesterase Isozymes in Pathogenesis of Murine Nephrogenic Diabetes Insipidus
|Title:||Role of cAMP-Phosphodiesterase Isozymes in Pathogenesis of Murine Nephrogenic Diabetes Insipidus|
|Authors:||Homma, Sumiko; Gapstur, Susan M.; Coffey, Aline K.; Valtin, Heinz; Dousa, Thomas P.|
|Publisher:||American Journal of Physiology|
|Date Published:||August 01, 1991|
This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
The collecting duct (CD) has three sections: (1) the innermost section, called the inner medullary CD (IMCD), (2) the next most inner section, the outer medullary CD (OMCD), and (3) the outermost section, the cortical CD (CCD). Their previous research led Homma, et al., to test whether high levels of certain enzymes of nucleotide phosphodiesterase PDE, specifically PDE-III and PDE-IV, is what is responsible for the collecting ducts of mice with inherited nephrogenic diabetes insipidus (NDI) being unable to respond to AVP.
The authors speculated that PDE-III and PDE-IV broke down cAMP before it could carry out its step in the molecular sequence that allows water reabsorption and urine concentration in the collecting duct. To test their hypothesis, the authors dissected the kidneys of NDI mice, separating them into IMCD, OMCD and CCD. By separating the CD into its component parts, the authors could measure more precisely the level and type of PDE activity in each part. Kidneys from normal mice were prepared identically to serve as a control group.
The authors found there was a significantly higher level of PDE activity that rapidly degrades cAMP in NDI mice than in the control mice. This held true for all segments of the CD, especially the IMCD. Now the authors wanted to confirm that of all the different PDE enzymes, it was PDE-IV and PDE-III that was active in the CD. To do this, they infused the dissected CDs with rolipram, which inhibits PDE-IV; cilostamide, which inhibits PDE-III; and IBMX, which inhibits all PDE.
IBMX inhibited PDE to a similar degree in both control and NDI mice CDs. Rolipram significantly inhibited PDE activity in the IMCD of NDI mice. So did cilostamide, but to a lesser extent. There was no such effect in the control IMCD. The same pattern held true for the OMCD of NDI mice, though the difference was less distinct.
Next, the authors administered a stimulatory dose of AVP to both the NDI and control CD tissues. This did not increase cAMP levels in the NDI tissues, whereas it did in the control tissues. When they added rolipram to the NDI IMCD tissue, then administered AVP, there was a five-fold increase in cAMP accumulation. Though there was no cAMP increase when cilostamide was added, when both cilostamide and rolipram were added to the NDI mice tissue, the cAMP accumulation rose twice as much as with rolipram alone. Similar results were found in the CCD of NDI mice. This indicated that when PDE-IV and PDE-III were inhibited, cAMP was not degraded at an abnormally rapid rate
This showed that it was high levels of PDE-IV and, to a lesser extent, PDE-III that was degrading cAMP before it could signal AQP2s to insert themselves in CD cell membranes.