Project: Research project

Project Details


Most studies of diabetic nephropathy have not focused on the proximal
tubule, although adaptations of this nephron segment to high glucose loads
may cause tubular injury. In diabetes, hyperglycemia augments the filtered
load of glucose to the tubule, and diminishes the tubule/glucose gradient
necessary for facilitative glucose efflux. In vitro, Na+-dependent luminal
influx (via Na+-GLUT) is decreased, although in vivo, the mass action
effect derived from the high glucose load augments glucose influx. We
propose to test the hypothesis that the proximal tubule maintains
transtubular glucose flux by adaptations of the basolateral transporters
(low Km GLUT 1 and high Km GLUT 2) at the level of gene transcription,
resulting in depressed levels of GLUT 1 mRNA and protein, and increased
levels of GLUT 2 mRNA and protein. This critical adaptation causes glucose
to increase in the tubule due to the higher efflux Km of overexpressed GLUT
2. In this manner, the tubule/glucose gradient (the energy source for
facilitative glucose efflux) is restored. However, the tubular glucose
(and osmolar) load is increased, which may promote glucose flux through the
polyol pathway. We plan to test the hypothesis with time course
experiments using the streptozotocin diabetic rat model. We will evaluate
the effect of glucose and insulin on the adaptation by measuring changes in
GLUT 1 & MRNA, and protein plus GLUT activity in tubules from diabetic rats
treated with insulin (lower glucose and higher insulin) and phlorizin
(lower glucose and low insulin). The molecular mechanism of the
adaptations will be assessed. The regulation of GLUT 1 & 2 gene
transcription by tubular nuclear factors will be examined in diabetic rats,
with the intent of identifying the trans acting factors responsible for the
adaptation. To support the hypothesis, the role of glucose influx and Na+
flux will be examined: Na+ -GLUT mRNA and protein plus Na+ -GLUT function
will be measured as a function of time. Moreover, since diabetes also
increases Na+ influx in vivo, we will measure Na+ /K+ ATPase (alpha1) mRNA,
Na+ pump number and activity. We believe that this information may prove
valuable for the development of strategies to arrest diabetic nephropathy.
Effective start/end date9/30/929/30/97


  • National Institutes of Health
  • National Institutes of Health: $121,089.00
  • National Institutes of Health


  • Medicine(all)

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