Project: Research project

Project Details


Following the reduction of renal mass, adaptive alterations in
both glomerular and tubular functions occur in surviving nephrons.
There is increasing recognition that such adaptation exerts
injurious effects, and provide pathways for progressive nephron
damage. The cellular and molecular events arising out of these
adaptive processes, which culminate in renal injury, are poorly
understood. The aim of this revised research proposal is to
explore the role of three well defined humoral systems in
adaptation and injury in the glomerular microcirculation following
the loss of renal mass, with special emphasis on glomerular
hemodynamic alterations. First, we will investigate whether
augmented synthetic rates of both the vasodilatory and
vasoconstrictor prostanoids, which we have recently described in
the remnant nephron, determine the pattern of hemodynamic
response of the remnant microcirculation to alterations in
perfusion pressure. We will examine the dependency of the renal
functional reserve of the subtotally nephrectomized kidney on the
capacity for vasodilatory prostaglandin synthesis. We will
characterize the functional effects of augmented thromboxane
synthesis on the glomerular microcirculation of the remnant
kidney and examine whether such increased production of
thromboxanes lead to alterations in permselectivity. These
functional studies would be coupled with studies examining the
humoral mechanisms underlying augmented prostanoid synthetic
rates. Secondly, we will explore the role of platelet derived
growth factor (PDGF) as a mechanism by which alterations in
glomerular hemodynamics lead to glomerular sclerosis. We
hypothesize that the heightened pressures and flows of the
glomerular microcirculation lead to injury to the capillary
endothelium thereby inducing the adhesion of platelets,
subsequent aggregation, and discharge of PDGF into the
surrounding tissues. We further hypothesize that in view of the
well established role of PDGF in promoting vascular injury, such
heightened release of PDGF may represent an important
mechanism for ongoing glomerular injury in surviving nephrons.
Finally, we will explore the role of the complement system in
determining the alterations in glomerular hemodynamics and
permselectivity that attend reduction of renal mass, with a
special emphasis on the complement components, amidated C3
and the terminal attack complex, C5b-9. The mechanism of
ammonia triggered, complement mediated tissue injury as a
pathway by which the level of dietary protein intake dictates the
severity of renal injury will also be explored. In summary, these
studies would provide greater insights into the role of these
humoral systems in adaptation and injury in surviving glomeruli
and hopefully would suggest therapeutic measures by which the
progression of renal disease can be retarded.
Effective start/end date3/1/882/28/94


  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institutes of Health


  • Medicine(all)


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