CELLULAR ACTION OF VASOPRESSIN IN THE KIDNEY

Project: Research project

Project Details

Description

The objective of this proposal is to determine the regulatory role of cAMP
phosphodiesterase isozymes (PDEs) in renal cells, namely in cells of inner
medullary collecting ducts (IMCD). We will test the hypothesis that cAMP-
mediated vasopressin (AVP) effects are modulated by specific PDE isozymes
via action of other 2nd messengers (Ca2+, cGMP), and extrarenal hormones,
namely glucocorticoids (GCD). In hereditary strain of mice with
nephrogenic diabetes insipidus (NDI mice), excessive and/or anomalous cAMP
PDE(s) account for complete resistance to AVP, a paradigm of essential role
of PDEs in cAMP-mediated action of AVP. Specific objectives include: 1) To identify PDEs which control AVP-dependent cAMP pool(s) in IMCD cells.
To define the mechanism by which cAMP generated in response to AVP by
acting on PDEs autoregulates the AVP response. To clarify the mechanism by
which other hormones (e.g. bradykinin) modulate action of AVP by changing
activities of PDEs via other 2nd messengers (cGMP, Ca2+i). 2) To elucidate how glucocorticoids (GCD) regulate the response of IMCD
cells to AVP at the step of the PDEs. We will determine which one of PDE
isozymes is down-regulated by GCD, and we will delineate the molecular-
biochemical mechanism of GCD effect upon PDE in IMCD cells. 3) To determine the mechanism by which PDE isozyme(s) of type-IV, present
in IMCD cells of NDI mice, prevents cAMP accumulation and the end-response
to AVP. a) We will explore whether higher PDE-IV activity is due to increased
quantum of enzyme protein, mRNA, transcription or translation rates in PDE-
IV synthesis, or to post-translational modification. Also, whether a
mutant PDE-IV with high Vmax or resistance to proteolysis may account for
high PDE-IV activity. b) We will test whether stable transfection of cells in vitro by PDE-IV
gene will reproduce the resistance to AVP as in NDI mice. In studies on
PDE-IV - transfected cells, we will determine, in general, the relationship
between cAMP response of IMCD cells to AVP and endogenous activity of PDE-
IV isozymes. These studies will be conducted on IMCD cells freshly prepared from rat,
rabbit or mouse kidneys, rat IMCD cells grown in primary or continuous in
vitro culture, and on established epithelial cell lines.
StatusFinished
Effective start/end date1/1/7512/31/09

Funding

  • National Institutes of Health: $295,798.00
  • National Institutes of Health: $248,287.00
  • National Institutes of Health: $241,056.00
  • National Institutes of Health: $311,963.00
  • National Institutes of Health: $304,632.00
  • National Institutes of Health: $234,034.00
  • National Institutes of Health: $289,882.00
  • National Institutes of Health: $311,963.00

ASJC

  • Medicine(all)

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