• Anderson, Sharon (PI)

Project: Research project

Project Details


The renin-angiotensin system (RAS) has been implicated in the
pathogenesis of diabetic glomerulopathy. The goal of this project is to
explore the relationships and interactions of the systemic and intrarenal
renin-angiotensin systems, to define their different regulatory
mechanisms, and to determine the site-specific roles of this hormonal
system in the modulation of glomerular hemodynamic function in the
diabetic kidney. Rationale: (1) Though plasma renin is normal,
circulating levels of Angiotensin II (Ang II) are elevated in diabetic
rats, indicating discordance of the systemic renin-angiotensin axis
(RAS). Origins, mediators, and regulatory consequences of this newly
recognized abnormality remain to be explored. (2) Biochemical, molecular
biologic, and immunohistochemical studies all indicate heightened
activity of the intrarenal RAS, disproportionate to the plasma RAS, as
well as redistribution of renal RAS components. More precise
localization and quantitation of various RAS components is required to
determine their site-specific roles. (3) Though RAS blockade influences
renal function, the primary hemodynamic problem (afferent arteriolar
vasodilation) must be under the influence of other hormonal systems.
General hypothesis: High Ang II levels result from increased activity
of non-classical processing pathways, and/or contributions of tissue
processing pathways, and may be influenced by interrelated vasodilators.
Localized heightened activity of the intrarenal RAS, particularly in the
glomeruli and renal vasculature, contributes to local hemodynamic
regulation. However, increased RAS activity also provides a stimulus to
counter-regulatory vasodilator systems (the kallikrein-kinin system and
endothelial derived relaxing factor), which dilate the afferent arteriole
and thereby also contribute to the hemodynamic adaptations. Specific
aims: (1) To localize the site(s) of altered RAS component processing,
by determining whether they result from altered processing pathways,
disproportionate contribution of the extrarenal tissue RAS, and/or
altered degradation; (2) to determine whether intrarenal Ang II formation
and action are increased in the diabetic kidney, and the role of systemic
Ang II levels in regulating the intrarenal RAS; (3) to determine whether
Ang II stimulates activity of the kallikrein-kinin system and
endothelial-derived relaxing factor, and to determine the
interrelationships among these vasodilators and the RAS in terms of
hemodynamic and hormonal regulation. To achieve these aims, we will use
an integrated biochemical, molecular biologic, immunohistochemical, and
physiologic approach. Joining these investigative tools together will
provide a novel and powerful approach to understanding the pathogenesis
of diabetic microangiopathy, potentially allowing more specific and
effective prevention of this leading cause of end stage renal disease and
Effective start/end date7/15/936/30/97


  • National Institutes of Health: $189,365.00


  • Medicine(all)


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