Project: Research project

Project Details


The long term goal of our investigations is elucidation of the
cellular mechanism by which vasopressin (VP) regulates H2O
permeability in in collecting tubules (CT) and the cellular
pathogenesis of nephrogenic diabetes insipidus (NDI). In
particular, we will clarify the role of cAMP phosphodiesterase
(PDE) and cAMP-protein kinase (cA-PK) isozyme systems as an
essential link in the pathway which connects V2-receptor signal at
the basolateral membrane with H2O permeability end-response at
luminal membrane (LM). Further, we will identify the defect(s) of
PDE and cA-PK system in mice with hereditary sever NDI.
Specific objectives include:
1. The determination of basic properties and modulatory role of
cyclic 3', 5'-nucleotide phosphodiesterases (PDE) isozymes in
cortical, medullary and papillary subsegments of CT. The studies
will focus on the a) acute modulatory effects of atrial natriuretic
peptide (ANP) via cGMP b) long-term effects of glucocorticoids
and c) pharmacologic effects of novel "second generation"
synthetic PDE inhibitors.
2. To elucidate segmental localization, isozyme composition, and
dynamics of enzymes and modulators cAMP-protein
phosphorylation system. Further, we will identify, using in situ
phosphorylation system, endogenous protein substrate(s) with
special attention to i) cytoskeletal and contractile protein, ii) the
feedback effect on PDE and V2-receptor/adenylate cyclase
complex, and iii) glycolytic and glycogenolytic enzymes.
3. To clarify role of PDE isozymes in refractoriness of CT of NDI
mice to VP. Studies will design aimed pharmacologic correction
by new synthetic compounds and by glucocorticoids. We will
explore possible anomalies in cA-PK and their relation to PDE in
CT of NDI mice.
Studies will be conducted on microdissected subsegments of
collecting tubules from mouse and rat kidney, and on cells from
these segments grown in primary culture.

In short, the outlined studies will decipher the role of PDE and
cA-PK isozymes in intracellular transmission of the VP-generated
cAMP signal in CT, and discover anomalies at these steps as a
cause of resistance to antidiuretic action of VP in NDI mice.
Effective start/end date1/1/7512/31/09


  • Medicine(all)