REGULATION OF SERUM PROTEIN COMPOSITION IN NEPHROSIS

Project: Research project

Description

The nephrotic syndrome is characterized by altered glomerular
permselectivity causing the urinary loss of proteins of intermediate
molecular weight (MW). Although albumin synthesis is increased by over 3
fold, its serum concentration decreases to less than 25% of normal, causing
a fall in serum oncotic pressure (pl). In contrast to albumin, the serum
concentration of many high MW proteins is increased in nephrosis, helping
to defend pl, as well as in rats with hereditary analbuminemia (HA),
animals with no significant urinary protein loss. Proteins in intermediate
NW (transferrin, gamma globulin and a globulins) are also increased in HA
rats, suggesting that reduced serum pl rather than either urinary protein
loss or increased albumin synthesis is the stimulus for increased
production of both intermediate and high MW proteins. We hypothesize that
serum pl regulates the synthesis of a specific array of acute phase
reactant proteins , and further that this control mechanism acts at the
level of gene transcription. To test the hypothesis we will determine the
relationship between pl and the rate of synthesis and catabolism of a group
of acute phase reactant proteins of a range of MW's (alpha1AG, alpha1
antitrypsin, transferrin, alpha2 macroglobulin), and determine the hepatic
steady state levels and rate of transcription of each species of mRNA in
two experimental animal models: 1) Sprague Dawley rats (SD) with the
nephrotic syndrome: a model of reduced pl caused by urinary protein loss,
and 2) HA rats: a model of reduced pl with no external protein loss. We
will further determine whether increasing serum pl to normal in nephrotic
rats and rats with HA by the infusion of hetastarch or
polyvinylpyrrolodone, suppresses increased synthesis of these proteins and
of their mRNA's. Using cultured hepatocytes isolated from normal SD and HA
rats, we will determine the relationship between pl and the synthesis of
albumin, transferrin, a1AG, a1 antitrypsin, a2 macroglobulin and steady
state concentration and rate of transcription of their mRNA's in response
to varying concentrations of albumin, PVP and hetastarch in the culture
medium. Since we have shown that dietary protein restriction prevents
enhanced expression of the albumin gene when serum pl is reduced, we will
also determine whether protein restriction modulates the response of other
proteins to reduced serum pl. If these studies indicate that serum pl
regulates the synthesis of an array of proteins at the level of gene
transcription, we will initiate molecular studies to define the factor(s)
which control this response.
StatusFinished
Effective start/end date2/15/9012/31/95

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,099,939.00
  • National Institutes of Health

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Nephrosis
Blood Proteins
Albumins
Proteins
Serum
Transferrin
Hydroxyethyl Starch Derivatives
Acute-Phase Proteins
Messenger RNA
Sprague Dawley Rats
alpha-Macroglobulins
Nephrotic Syndrome
Macroglobulins
Protein Array Analysis
Dietary Proteins
gamma-Globulins
Globulins
Hepatocytes
Animal Models

ASJC

  • Medicine(all)