Rationale: Male gender is an important risk factor for progression of diabetic nephropathy, the leading cause of end-stage renal disease. Mechanisms by which the relative ratio of estrogen to androgen specifically impacts renal dysfunction and fibrosis are not well defined. There is strong rationale to study gender hormones: to understand the mechanisms by which estrogens protect, and/or androgens injure, the kidney; to utilize recent advances in the vascular biology of gender hormones, as they pertain to the kidney; and to determine the utility of new hormonal derivatives which may be safer and free of side effects, in both men and women. Many cellular actions of sex steroids have not been tested in the kidney, and are likely to differentially affect the discrete intrarenal compartments (glomerular/vascular vs. tubulointerstitial) which play a role in loss of renal function. We will explore the role of classical and novel gender hormones in experimental diabetes. To achieve our aims, we will use complementary physiological, biochemical, molecular, and immunohistochemical approaches, joining in vivo and in vitro studies. Hypotheses: (1) Gender-related protection against diabetic nephropathy is related to the protective effect of endogenous estrogen and its metabolites; (2) estrogenic compounds limit the activity of the renin-angiotensin system (RAS), and act synergistically with drugs which block the RAS; (3) estrogenic compounds shift the balance in endothelial-derived vasoactive mediators, with a net increase in nitric oxide (NO) action, and reduction in endothelin-1 (ET); and (4) actions of gender hormones relate in part relate to their effects on vascular endothelial growth factor (VEGF), and its interactions with fibrotic mediators.
Specific Aims : In experimental diabetes, (1) to determine the contribution of gender to susceptibility to diabetic glomerular and tubulointerstitial injury, and whether manipulation of gender hormones alters the course of disease; (2) to examine the interactions among gender hormones and the renin-angiotensin system on hemodynamics, vasoactive mediators, and fibrosis mediators; (3) to examine the interactions among gender hormones and the nitric oxide/endothelin systems, on hemodynamics, vasoactive mediators, and fibrosis mediators; and (4) to determine the role of VEGF in altering the balance of matrix forming and degrading enzymes in experimental diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063231-04
Application #
7066681
Study Section
General Medicine B Study Section (GMB)
Program Officer
Meyers, Catherine M
Project Start
2003-07-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$211,012
Indirect Cost
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Anderson, Sharon; Chapman, Justin G; Oyama, Terry T et al. (2010) Effect of orchiectomy on renal function in control and diabetic rats with chronic inhibition of nitric oxide. Clin Exp Pharmacol Physiol 37:19-23
Anderson, Sharon; Komers, Radko (2009) Inhibition of the renin-angiotensin system: is more better? Kidney Int 75:12-4
Zdychova, Jana; Kazdova, Ludmila; Pelikanova, Terezie et al. (2008) Renal activity of Akt kinase in obese Zucker rats. Exp Biol Med (Maywood) 233:1231-41
Komers, Radko; Schutzer, William; Xue, Hong et al. (2007) Effects of p38 mitogen-activated protein kinase inhibition on blood pressure, renal hemodynamics, and renal vascular reactivity in normal and diabetic rats. Transl Res 150:343-9
Komers, Radko; Lindsley, Jessie N; Oyama, Terry T et al. (2007) Renal p38 MAP kinase activity in experimental diabetes. Lab Invest 87:548-58
Komers, Radko; Schutzer, William E; Reed, John F et al. (2006) Altered endothelial nitric oxide synthase targeting and conformation and caveolin-1 expression in the diabetic kidney. Diabetes 55:1651-9
Komers, Radko; Zdychova, Jana; Cahova, Monika et al. (2005) Renal cyclooxygenase-2 in obese Zucker (fatty) rats. Kidney Int 67:2151-8
Komers, Radko; Lindsley, Jessie N; Oyama, Terry T et al. (2004) Effects of long-term inhibition of neuronal nitric oxide synthase (NOS1) in uninephrectomized diabetic rats. Nitric Oxide 11:147-55