PATHOPHYSIOLOGY OF DIABETIC NEPHROPATHY
Principal Investigator: S Anderson
Abstract: 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.
Funding Period: 2003-07-01 - 2008-04-30
more information: NIH RePORT
- Renal cyclooxygenase-2 in obese Zucker (fatty) ratsRadko Komers
Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
Kidney Int 67:2151-8. 2005..Unlike type 1 diabetes, renal COX has not been studied in models of type 2 diabetes...
- Altered endothelial nitric oxide synthase targeting and conformation and caveolin-1 expression in the diabetic kidneyRadko Komers
Division of NephrologyHypertension PP262, Oregon Health and Science University, 3314 SW US Veterans Hospital Rd, Portland, OR 97239, USA
Diabetes 55:1651-9. 2006..In summary, we observed diabetes-mediated alterations in eNOS and CAV-1 expression that are consistent with the view of decreased bioavailability of renal eNOS-derived NO...
- Renal p38 MAP kinase activity in experimental diabetesRadko Komers
Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, OR 97239 2940, USA
Lab Invest 87:548-58. 2007..p38 activation in diabetes is likely to occur via multiple pathways and cannot be explained by downregulation of MKP-1...
- Effects of p38 mitogen-activated protein kinase inhibition on blood pressure, renal hemodynamics, and renal vascular reactivity in normal and diabetic ratsRadko Komers
Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, Ore 97239, USA
Transl Res 150:343-9. 2007..The observed effects of p38 inhibition could be mediated at least in part by enhancement of endothelium-dependent vasodilation...
- Renal activity of Akt kinase in obese Zucker ratsJana Zdychova
Institute for Clinical and Experimental Medicine, Prague, Czech Republic
Exp Biol Med (Maywood) 233:1231-41. 2008..These data suggest that DM2 is associated with selective IR in the kidney, allowing pro-growth signaling via mTOR, whereas potentially protective effects mediated by eNOS are blunted...
- Inhibition of the renin-angiotensin system: is more better?Sharon Anderson
Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, Oregon, USA
Kidney Int 75:12-4. 2009..They linked the reductions of proteinuria with regression of mesangial expansion. More advanced lesions were not affected. There were no dose-response renal effects of losartan...
- Effect of orchiectomy on renal function in control and diabetic rats with chronic inhibition of nitric oxideSharon Anderson
Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, Oregon 97239 2940, USA
Clin Exp Pharmacol Physiol 37:19-23. 2010..This suggests that testosterone reduction does not attenuate the deleterious impact of the diabetic metabolic milieu in the kidney...