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Science 3 May 1996:
Vol. 272. no. 5262, pp. 728 - 731
DOI: 10.1126/science.272.5262.728
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Reports

Amelioration of Vascular Dysfunctions in Diabetic Rats by an Oral PKC beta  Inhibitor

Hidehiro Ishii, Michael R. Jirousek, Daisuke Koya, Chikako Takagi, Pu Xia, Allen Clermont, Sven-Erik Bursell, Timothy S. Kern, Lawrence M. Ballas, William F. Heath, Lawrence E. Stramm, Edward P. Feener, George L. King *

The vascular complications of diabetes mellitus have been correlated with enhanced activation of protein kinase C (PKC). LY333531, a specific inhibitor of the beta  isoform of PKC, was synthesized and was shown to be a competitive reversible inhibitor of PKC beta 1 and beta 2, with a half-maximal inhibitory constant of sim 5 nM; this value was one-fiftieth of that for other PKC isoenzymes and one-thousandth of that for non-PKC kinases. When administered orally, LY333531 ameliorated the glomerular filtration rate, albumin excretion rate, and retinal circulation in diabetic rats in a dose-responsive manner, in parallel with its inhibition of PKC activities.

H. Ishii, D. Koya, C. Takagi, P. Xia, A. Clermont, S.-E. Bursell, E. P. Feener, G. L. King, Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA.
M. R. Jirousek, W. F. Heath, L. E. Stramm, Lilly Laboratories, Indianapolis, IN 46285, USA.
T. S. Kern, Department of Ophthalmology, University of Wisconsin, Madison, WI 53706, USA.
L. M. Ballas, Sphinx Pharmaceutical, Durham, NC 27707, USA.
* To whom correspondence should be addressed.


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M. R. Loeken (2006)
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D. C. Braun, S. H. Garfield, and P. M. Blumberg (2005)
J. Biol. Chem. 280, 8164-8171
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C. Rask-Madsen and G. L. King (2005)
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Pathogenetic Mechanisms of Diabetic Nephropathy.
F. P. Schena and L. Gesualdo (2005)
J. Am. Soc. Nephrol. 16, S30-S33
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From Hyperglycemia to Diabetic Kidney Disease: The Role of Metabolic, Hemodynamic, Intracellular Factors and Growth Factors/Cytokines.
B. F. Schrijvers, A. S. De Vriese, and A. Flyvbjerg (2004)
Endocr. Rev. 25, 971-1010
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Overexpression of human heme oxygenase-1 attenuates endothelial cell sloughing in experimental diabetes.
N. G. Abraham, R. Rezzani, L. Rodella, A. Kruger, D. Taller, G. Li Volti, A. I. Goodman, and A. Kappas (2004)
Am J Physiol Heart Circ Physiol 287, H2468-H2477
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Masterclass series in peripheral arterial disease: Vascular risk: diabetes.
D. J Collinson, R. Rea, and R. Donnelly (2004)
Vascular Medicine 9, 307-310
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Attenuation of Extracellular Matrix Accumulation in Diabetic Nephropathy by the Advanced Glycation End Product Cross-Link Breaker ALT-711 via a Protein Kinase C-{alpha}-Dependent Pathway.
V. Thallas-Bonke, C. Lindschau, B. Rizkalla, L. A. Bach, G. Boner, M. Meier, H. Haller, M. E. Cooper, and J. M. Forbes (2004)
Diabetes 53, 2921-2930
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Chronic Oxidative Stress as a Central Mechanism for Glucose Toxicity in Pancreatic Islet Beta Cells in Diabetes.
R. P. Robertson (2004)
J. Biol. Chem. 279, 42351-42354
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Diabetic Retinopathy.
D. S. Fong, L. P. Aiello, F. L. Ferris III, and R. Klein (2004)
Diabetes Care 27, 2540-2553
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High concentration of glucose inhibits glomerular endothelial eNOS through a PKC mechanism.
S. Chu and H. G. Bohlen (2004)
Am J Physiol Renal Physiol 287, F384-F392
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Diminished Loss of Proteoglycans and Lack of Albuminuria in Protein Kinase C-{alpha}--Deficient Diabetic Mice.
J. Menne, J.-K. Park, M. Boehne, M. Elger, C. Lindschau, T. Kirsch, M. Meier, F. Gueler, A. Fiebeler, F. H. Bahlmann, et al. (2004)
Diabetes 53, 2101-2109
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H.-Y. Park, H. Wu, C. E. Killoran, and B. A. Gilchrest (2004)
J. Cell Sci. 117, 3659-3668
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Selective Inhibition of Protein Kinase C{beta}2 Prevents Acute Effects of High Glucose on Vascular Cell Adhesion Molecule-1 Expression in Human Endothelial Cells.
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R. Fernandes, H. Girao, and P. Pereira (2004)
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E. Verrier, L. Wang, C. Wadham, N. Albanese, C. Hahn, J. R. Gamble, V. K. K. Chatterjee, M. A. Vadas, and P. Xia (2004)
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   Abstract »    Full Text »    PDF »
Effect of PKC{beta} on Retinal Oxygenation Response in Experimental Diabetes.
H. Luan, M. Leitges, R. R. Gupta, D. Pacheco, A. Seidner, J. Liggett, Y. Ito, R. Kowluru, and B. A. Berkowitz (2004)
Invest. Ophthalmol. Vis. Sci. 45, 937-942
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Protein kinase {beta}II in Zucker obese rats compromises oxygen and flow-mediated regulation of nitric oxide formation.
H. G. Bohlen (2004)
Am J Physiol Heart Circ Physiol 286, H492-H497
   Abstract »    Full Text »    PDF »
Hexosamines and TGF-{beta}1 use similar signaling pathways to mediate matrix protein synthesis in mesangial cells.
L. P. Singh, K. Green, M. Alexander, S. Bassly, and E. D. Crook (2004)
Am J Physiol Renal Physiol 286, F409-F416
   Abstract »    Full Text »    PDF »
Diabetic Retinopathy.
R. N. Frank (2004)
N. Engl. J. Med. 350, 48-58
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Protein kinase C inhibition and diabetic retinopathy: a shot in the dark at translational research.
R Donnelly, I Idris, and J V Forrester (2004)
Br J Ophthalmol 88, 145-151
   Abstract »    Full Text »    PDF »
Biochemical Pathways for Microvascular Complications of Diabetes Mellitus.
S. M Setter, R K. Campbell, and C. J Cahoon (2003)
Ann. Pharmacother. 37, 1858-1866
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Intermittent High Glucose Enhances Apoptosis Related to Oxidative Stress in Human Umbilical Vein Endothelial Cells: The Role of Protein Kinase C and NAD(P)H-Oxidase Activation.
L. Quagliaro, L. Piconi, R. Assaloni, L. Martinelli, E. Motz, and A. Ceriello (2003)
Diabetes 52, 2795-2804
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Diabetic Retinopathy and Diabetic Macular Edema: Pathophysiology, screening, and novel therapies.
T. A. Ciulla, A. G. Amador, and B. Zinman (2003)
Diabetes Care 26, 2653-2664
   Abstract »    Full Text »    PDF »
Sensory Neurons With Activated Caspase-3 Survive Long-Term Experimental Diabetes.
C. Cheng and D. W. Zochodne (2003)
Diabetes 52, 2363-2371
   Abstract »    Full Text »    PDF »
Identification of a Common Risk Haplotype for Diabetic Nephropathy at the Protein Kinase C-{beta}1 (PRKCB1) Gene Locus.
S.-i. Araki, D. P.K. Ng, B. Krolewski, L. Wyrwicz, J. J. Rogus, L. Canani, Y. Makita, M. Haneda, J. H. Warram, and A. S. Krolewski (2003)
J. Am. Soc. Nephrol. 14, 2015-2024
   Abstract »    Full Text »    PDF »
Intracellular Na+ Regulates Dopamine and Angiotensin II Receptors Availability at the Plasma Membrane and Their Cellular Responses in Renal Epithelia.
R. Efendiev, C. E. Budu, A. R. Cinelli, A. M. Bertorello, and C. H. Pedemonte (2003)
J. Biol. Chem. 278, 28719-28726
   Abstract »    Full Text »    PDF »
Protein Kinase C-Dependent Increase in Reactive Oxygen Species (ROS) Production in Vascular Tissues of Diabetes: Role of Vascular NAD(P)H Oxidase.
T. Inoguchi, T. Sonta, H. Tsubouchi, T. Etoh, M. Kakimoto, N. Sonoda, N. Sato, N. Sekiguchi, K. Kobayashi, H. Sumimoto, et al. (2003)
J. Am. Soc. Nephrol. 14, S227-232
   Abstract »    Full Text »    PDF »
Extracellular Matrix Metabolism in Diabetic Nephropathy.
R. M. Mason and N. A. Wahab (2003)
J. Am. Soc. Nephrol. 14, 1358-1373
   Abstract »    Full Text »    PDF »
Glucose, Glycation, and RAGE: Implications for Amplification of Cellular Dysfunction in Diabetic Nephropathy.
T. Wendt, N. Tanji, J. Guo, B. I. Hudson, A. Bierhaus, R. Ramasamy, B. Arnold, P. P. Nawroth, S. F. Yan, V. D'Agati, et al. (2003)
J. Am. Soc. Nephrol. 14, 1383-1395
   Abstract »    Full Text »    PDF »
Characterization of Retinal Leukostasis and Hemodynamics in Insulin Resistance and Diabetes: Role of Oxidants and Protein Kinase-C Activation.
T. Abiko, A. Abiko, A. C. Clermont, B. Shoelson, N. Horio, J. Takahashi, A. P. Adamis, G. L. King, and S.-E. Bursell (2003)
Diabetes 52, 829-837
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Role of Protein Kinase C on the Expression of Platelet-Derived Growth Factor and Endothelin-1 in the Retina of Diabetic Rats and Cultured Retinal Capillary Pericytes.
T. Yokota, R. C. Ma, J.-Y. Park, K. Isshiki, K. B. Sotiropoulos, R. K. Rauniyar, K. E. Bornfeldt, and G. L. King (2003)
Diabetes 52, 838-845
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Delayed Treatment with Lithospermate B Attenuates Experimental Diabetic Renal Injury.
G. T. Lee, H. Ha, M. Jung, H. Li, S. W. Hong, B. S. Cha, H. Chul Lee, and a. Y. Dong Cho (2003)
J. Am. Soc. Nephrol. 14, 709-720
   Abstract »    Full Text »    PDF »
High Glucose Causes Upregulation of Cyclooxygenase-2 and Alters Prostanoid Profile in Human Endothelial Cells: Role of Protein Kinase C and Reactive Oxygen Species.
F. Cosentino, M. Eto, P. De Paolis, B. van der Loo, M. Bachschmid, V. Ullrich, A. Kouroedov, C. Delli Gatti, H. Joch, M. Volpe, et al. (2003)
Circulation 107, 1017-1023
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Protein Kinase C {beta} Inhibition Attenuates the Progression of Experimental Diabetic Nephropathy in the Presence of Continued Hypertension.
D. J. Kelly, Y. Zhang, C. Hepper, R. M. Gow, K. Jaworski, B. E. Kemp, J. L. Wilkinson-Berka, and R. E. Gilbert (2003)
Diabetes 52, 512-518
   Abstract »    Full Text »    PDF »


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