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Biophysical mechanisms in the pathogenesis of diabetic nephropathy

Award Number: R01DK061653
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2002
PERIOD OF PERFORMANCE END DATE: 01/31/2016

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Biophysical mechanisms in the pathogenesis of diabetic nephropathy - DESCRIPTION (provided by applicant): Overt diabetic nephropathy (DN) is very slow to develop, but once initiated progresses rapidly. We postulate that early in the course of diabetes, NO availability is increased in part due to the recruitment of the vascular NO2 as a NO source. NO likely protects against the adverse cellular effects of hyperglycemia and by dilating the efferent arteriole (EA) prevents glomerular hypertension (HTN). Thus, HTN mechanisms do not play a significant role during this slow initiation phase. However, with endothelial dysfunction and NO loss over time the EA constricts and there is a further upregulation of endothelium derived hyperpolarizing factor(s) (EDHF), which unlike NO, can only dilate the AA, but not the EA. This increase in EA>AA resistance results in glomerular HTN. EDHF also impairs myogenic autoregulation with further exacerbation of glomerular HTN and overt DN develops. Consistent with the hypothesis, preliminary data show that the Sprague-Dawley (SD) rats from the two major suppliers, Harlan (H) and Charles River (CR) differ greatly in NO availability (CR NO; H NO) and in their susceptibility to DN. Specific Aim 1 will test the hypothesis that the NO availability profile will evolve differentially during the temporal course of streptozotocin (STZ) diabetes in (H) and (CR) rats and changes in NO availability will be paralleled by postulated changes in renal endothelial hemodynamic function (NO, EDHF and prostaglandin dependent dilation), BP transmission parameters and DN susceptibility. Additionally, the hypothesis will be tested that the BP response to L-NAME at 10-14 days after diabetes will predict the subsequent severity of DN in individual rats at 4-6 months. Specific Aim 2 will test if interventions that increase NO availability in (H) rats (dietary nitrite and/or arginine supplementation, tempol, tetrahydrobiopterin) or reduce it in (CR) rats (nitrite free diet + L-NAME) have the predicted effects on DN. Additionally, parallels and differences between diabetic (H) rats and the diabetic eNOS-/-, which do develop advanced DN pathology will be assessed. Specific Aim 3 will use the in-vitro perfused hydronephrotic kidney model to test the hypothesis that DN is associated with EDHF > NO in the renal microcirculation resulting in a relative EA>AA vasoconstriction and increased PGC. Relevance these investigations should provide new insights into the roles of nitric oxide availability, endothelial dysfunction and increasing glomerular pressures as determinants of the course and susceptibility to DN.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2015 ( Subtotal = $0 )
2015	2014	CHICAGO ASSOCIATION FOR RESEARCH & ED IN SCIENCE	BLDG ONE RM C307PO BOX 250	HINES	IL	60141	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	3/4/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $260,051 )
2014	2014	CHICAGO ASSOCIATION FOR RESEARCH & ED IN SCIENCE	BLDG ONE RM C307PO BOX 250	HINES	IL	60141	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	3/21/2014	NON-COMPETING CONTINUATION	$260,051
														Subtotal = $260,051

Issue Date FY: 2013 ( Subtotal = $250,949 )
2013	2013	CHICAGO ASSOCIATION FOR RESEARCH & ED IN SCIENCE	BLDG ONE RM C307PO BOX 250	HINES	IL	60141	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	12/27/2012	NON-COMPETING CONTINUATION	$234,046
2013	2013	CHICAGO ASSOCIATION FOR RESEARCH & ED IN SCIENCE	BLDG ONE RM C307PO BOX 250	HINES	IL	60141	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	5/21/2013	NON-COMPETING CONTINUATION	$16,903
														Subtotal = $250,949

Issue Date FY: 2012 ( Subtotal = $260,051 )
2012	2012	CHICAGO ASSOCIATION FOR RESEARCH & ED IN SCIENCE	BLDG ONE RM C307PO BOX 250	HINES	IL	60141	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	3/9/2012	NON-COMPETING CONTINUATION	$260,051
														Subtotal = $260,051

Issue Date FY: 2011 ( Subtotal = $321,074 )
2011	2011	CHICAGO ASSOCIATION FOR RESEARCH & ED IN SCIENCE	BLDG ONE RM C307PO BOX 250	HINES	IL	60141	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	6/9/2011	COMPETING CONTINUATION	$39,692
2011	2011	CHICAGO ASSOCIATION FOR RESEARCH & ED IN SCIENCE	BLDG ONE RM C307PO BOX 250	HINES	IL	60141	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	3/4/2011	COMPETING CONTINUATION	$281,382
														Subtotal = $321,074

Issue Date FY: 2006 ( Subtotal = $189,155 )
2006	2006	LOYOLA UNIVERSITY MEDICAL CENTER	820 N MICHIGAN AVENUE	CHICAGO	IL	60611	COOK	USA	Kidney Diseases, Urology and Hematology Research	000	5	12/21/2005	NON-COMPETING CONTINUATION	$189,155
														Subtotal = $189,155

Issue Date FY: 2005 ( Subtotal = $193,707 )
2005	2005	LOYOLA UNIVERSITY MEDICAL CENTER							Kidney Diseases, Urology and Hematology Research	000	4	12/27/2004	NON-COMPETING CONTINUATION	$193,707
														Subtotal = $193,707

Issue Date FY: 2004 ( Subtotal = $193,707 )
2004	2004	LOYOLA UNIVERSITY MEDICAL CENTER							Kidney Diseases, Urology and Hematology Research	000	3	1/15/2004	NON-COMPETING CONTINUATION	$193,707
														Subtotal = $193,707

Issue Date FY: 2003 ( Subtotal = $193,707 )
2003	2003	LOYOLA UNIVERSITY MEDICAL CENTER	2160 SOUTH FIRST AVENUE	MAYWOOD	IL	60153	COOK	USA	Kidney Diseases, Urology and Hematology Research	000	2		NON-COMPETING CONTINUATION	$193,707
														Subtotal = $193,707

Issue Date FY: 2002 ( Subtotal = $242,545 )
2002	2002	LOYOLA UNIVERSITY MEDICAL CENTER	2160 SOUTH FIRST AVENUE	MAYWOOD	IL	60153	COOK	USA	Kidney Diseases, Urology and Hematology Research	000	1	4/8/2002	NEW	$242,545
														Subtotal = $242,545

Grand Total All Awards = $2,104,946

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Biophysical mechanisms in the pathogenesis of diabetic nephropathy

Award Number: R01DK061653

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/15/2002

PERIOD OF PERFORMANCE END DATE: 01/31/2016

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