Oliver Smithies

Personal Information
Title Professor
Expertise Nephropathy
Institution University of North Carolina
Data Summary
TypeCount
Grants/SubContracts 2
Progress Reports 6
Presentations 2
Publications 20
Protocols 1
Committees 2
Experiments 0
Strains 18
Models 2

Bradykinin, Nitric Oxide and Mitochondrial DNA Damage in Diabetic Complications
Grant Number: DK076131

Abstract: In our previous work we have demonstrated that genetic factors controlling the production of bradykinin (BK) and nitric oxide (NO) influence greatly the development of renal complications in mice made diabetic with streptozotocin (STZ) or by the Akita diabetogenic C86Y mutation in Ins 2. We also showed that diabetic nephropathy and several indicators of senescence increase progressively in the order wildtype < bradykinin receptor B2 null < Akita diabetic < B2 receptor null Akita diabetic. 8-OHdG content, point mutations and deletions in mitochondrial (mt) DNA increased in the same progression, as did indicators of oxidative stress. We now propose three specific aims and the generation of two new mouse models to determine the interplay between genetic factors that influence BK action, the production of NO, and diabetes-related increases in mutations in mtDNA. Specific aim 1 will determine the effect on diabetic complications of eliminating both BK receptors throughout the body, or in a tissue or cell specific manner; the effects of reducing oxidative stress in these mice will also be determined. Specific aim 2 will investigate the relationship between glomerular damage and mtDNA mutations in eNOS -/- diabetic mice in which we have found that oxidative stress is paradoxically less than in eNOS +/+ diabetic mice. Specific aim 3 will test the hypothesis that increasing the frequency of mtDNA mutations by introducing a proof reading defect into mitochondrial DNA polymerase gamma will exacerbate the complications in Akita diabetic mice even though oxidative stress is not further increased over that due to the diabetes alone.


Institution: University of North Carolina
9201 University City Blvd
Charlotte, NC
Fiscal Year:2006
Department:PATHOLOGY AND LAB MEDICINE
Project Start: 9/30/2006
Project End: 8/31/2011
ICD: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES

SubContract(s)


Molecular events during progression from microalbuminuria to diabetic nephropathy
Abstract The occurrence of microalbuminuria in diabetic individuals is a well established risk factor for subsequent progression to nephropathy. Interrupting or reversing this progression is the aim of clinicians who care for diabetic patients. Yet, at the subcellular and molecular levels, there is a clear gap in our understanding of this progression. I have two tools that put me in a unique position to fill this gap. The first tool is the superb and diverse collection of well-characterized diabetic mice developed by the AMDCC, some of which undergo the progression from microalbuminuria to diabetic nephropathy (DN). The second tool, developed by my group under an R21 grant, is a diverse collection of gold nanoparticles and fluorescent proteins, with molecular sizes covering the range of plasma proteins, which are directly visible by electron and confocal microscopy as they enter and traverse the kidney. Specific Aim 1 will take advantage of these tools to determine the degree to which the progression from microalbuminuria to overt albuminuria is the consequence of deterioration in the glomerular filtration barrier, as judged by changes in the ability of the glomerular basement membrane (GBM) to exclude molecules in a graded manner inversely related to their size. Specific Aim 2 will likewise determine the degree to which the progression is consequence of deterioration in tubular function, as judged by changes in the removal of macromolecules from the tubular fluid. We expect to obtain sufficient knowledge from our proposed pilot study to be able to assess the feasibility of applying the same procedures to evaluate the efficacy of new pharmaceutical interventions aimed at preventing or reversing the devastating progression of nephropathy that so frequently occurs in diabetics who develop microalbuminuria.


Progress Reports

Annual Reports

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Smithies, Oliver
2008Annual Report
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Smithies, Oliver (2007)
2007Annual Report
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Smithies, Oliver (2009)
2009Annual Report
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Smithies, Oliver (2010)
2010Annual Report
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Smithies, Oliver (2011)
2011Annual Report
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 PublicationAltmetricsSubmitted ByPubMed IDStatus

Year: 2014; Items: 1

 
The role of transforming growth factor ß1 in the regulation of blood pressure.
Matsuki K, Hathaway CK, Lawrence MG, Smithies O, Kakoki M
Current hypertension reviews, 2014 (10), 223 - 238
Submitted Externally
25801626
Published

Year: 2012; Items: 4

 
The kallikrein-kinin system and oxidative stress.
Kayashima Y, Smithies O, Kakoki M
Current opinion in nephrology and hypertension, 2012 (21), 92 - 96
22048723
Published
 
eNOS deficiency acts through endothelin to aggravate sFlt-1-induced pre-eclampsia-like phenotype.
Li F, Hagaman JR, Kim HS, Maeda N, Jennette JC, Faber JE, Karumanchi SA, Smithies O, Takahashi N
Journal of the American Society of Nephrology : JASN, 2012 (23), 652 - 660
22282588
Published
 
The kallikrein-kinin system in diabetic nephropathy.
Tomita H, Sanford RB, Smithies O, Kakoki M
Kidney international, 2012 (81), 733 - 744
22318421
Published
 
Null mutations at the p66 and bradykinin 2 receptor loci induce divergent phenotypes in the diabetic kidney.
Vashistha H, Singhal PC, Malhotra A, Husain M, Mathieson P, Saleem MA, Kuriakose C, Seshan S, Wilk A, Delvalle L, Peruzzi F, Giorgio M, Pelicci PG, Smithies O, Kim HS, Kakoki M, Reiss K, Meggs LG
American journal of physiology. Renal physiology, 2012 (303), F1629 - F1640
Submitted Externally
23019230
Published

Year: 2011; Items: 3

 
A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy.
Wang CH, Li F, Hiller S, Kim HS, Maeda N, Smithies O, Takahashi N
Proceedings of the National Academy of Sciences of the United States of America, 2011 (108), 2070 - 2075
21245338
Published
 
A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy.
Wang CH, Li F, Hiller S, Kim HS, Maeda N, Smithies O, Takahashi N
Proceedings of the National Academy of Sciences of the United States of America, 2011 (108), 2070 - 5
21245338
Published
 
Mitochondrial DNA polymerase editing mutation, PolgD257A, reduces the diabetic phenotype of Akita male mice by suppressing appetite.
Fox R, Kim HS, Reddick RL, Kujoth GC, Prolla TA, Tsutsumi S, Wada Y, Smithies O, Maeda N
Proceedings of the National Academy of Sciences of the United States of America, 2011 (108), 8779 - 8784
21555558
Published

Year: 2010; Items: 5

 
Diabetes regulates mitochondrial biogenesis and fission in mouse neurons.
Edwards JL, Quattrini A, Lentz SI, Figueroa-Romero C, Cerri F, Backus C, Hong Y, Feldman EL
Diabetologia, 2010 (53(1)), 160 - 169
19847394
Published
 
Abnormalities in signaling pathways in diabetic nephropathy.
Brosius FC, Khoury CC, Buller CL, Chen S
Expert review of endocrinology & metabolism, 2010 (5(1)), 51 - 64
20224802
Published
 
Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice.
Kakoki M, Sullivan KA, Backus C, Hayes JM, Oh SS, Hua K, Gasim AM, Tomita H, Grant R, Nossov SB, Kim HS, Jennette JC, Feldman EL, Smithies O
Proceedings of the National Academy of Sciences of the United States of America, 2010 (107), 10190 - 10195
20479236
Published
 
Loss of bradykinin signaling does not accelerate the development of cardiac dysfunction in type 1 diabetic akita mice.
Wende AR, Soto J, Olsen CD, Pires KM, Schell JC, Larrieu-Lahargue F, Litwin SE, Kakoki M, Takahashi N, Smithies O, Abel ED
Endocrinology, 2010 (151), 3536 - 3542
20501666
Published
 
Elevated tissue factor expression contributes to exacerbated diabetic nephropathy in mice lacking eNOS fed a high fat diet
F . L I , C.-H. WANG, J .-G. WANG, T. THAI , G. BOYSEN, L . XU, A. L . TURNER, A. S . WOLBERG, N. MACKMAN, N. MAEDA and N. TAKAHASHI
Journal of thrombosis and haemostasis : JTH, 2010 (8), 2122 - 2132
20626618
Published

Year: 2009; Items: 3

 
Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice.
Ghosh S, Khazaei M, Moien-Afshari F, Ang LS, Granville DJ, Verchere CB, Dunn SR, McCue P, Mizisin A, Sharma K, Laher I
American journal of physiology. Renal physiology, 2009 (296(4)), F700 - F708
19144689
Published
 
The kallikrein-kinin system in health and in diseases of the kidney
Kakoki M, Smithies O
Kidney international, 2009
19190676
Published
 
Mouse Models of Diabetic Nephropathy: A Midstream Analysis from the Diabetic Complications Consortium
Frank C. Brosius IIIa, Charles E. Alpersb, Erwin P. Bottingerc, Matthew D. Breyerd, ThomasM. Coffmane, Susan B. Gurleye, Raymond C. Harrisf, Masao Kakokig, Matthias Kretzler, Edward H. Leiterh, Moshe Levii, Richard A. McIndoej, Kumar Sharmak, Oliver Smithiesg, Katalin Susztakl, Nobuyuki Takahashig, Takamune Takahashif
Journal of the American Society of Nephrology : JASN, 2009 (20(12)), 2503 - 2512
19729434
Published

Year: 2007; Items: 2

 
Tandem mass spectrometry measurements of creatinine in mouse plasma and urine for determining glomerular filtration rate
Takahashi N, Boysen G, Li F, Li Y, Swenberg JA
Kidney international, 2007 (71), 266 - 271
17149371
Published
 
Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury
Kakoki M, McGarrah RW, Kim H-S, Smithies O
Proceedings of the National Academy of Sciences of the United States of America, 2007 (104), 7576 - 7581
17452647
Published

Year: 2006; Items: 1

 
Senescence-associated phenotypes in Akita diabetic mice are enhanced by absence of bradykinin B2 receptors
Kakoki M, Kizer CM, Yi X, Takahashi N, Kim H-S, Bagnell CR, Edgell CJS, Maeda N, Jennette JC, Smithies O
The Journal of clinical investigation, 2006 (116), 1302 - 1309
16604193
Published

Year: 2004; Items: 1

 
Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor.
Kakoki M, Takahashi N, Jennette JC, Smithies O
Proceedings of the National Academy of Sciences of the United States of America, 2004 (101), 13302 - 13305
15326315
Published

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No experiments found.