2007 JASN IMPACT FACTOR 7.111	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by KAPOR-DREZGIC, J. Articles by WHITESIDE, C. Search for Related Content PubMed PubMed Citation Articles by KAPOR-DREZGIC, J. Articles by WHITESIDE, C.

Effect of High Glucose on Mesangial Cell Protein Kinase C- and - is Polyol Pathway-Dependent

JOVANA KAPOR-DREZGIC^*, XIAOPENG ZHOU^*, TETSUYA BABAZONO, JOHN A. DLUGOSZ^*, THOMAS HOHMAN and CATHARINE WHITESIDE^*

^* Institute of Medical Science and Department of Medicine, University of Toronto, Canada
Tokyo Women's Medical College, Tokyo, Japan
Wyeth-Ayerst Research, Princeton, New Jersey.

Correspondence to Dr. Catharine Whiteside, Medical Sciences Building, Room 7302, 1 King's College Circle, University of Toronto, Toronto, Ontario, Canada, M5S 1A8. Phone: 416-340-4140; Fax: 416-586-9827; E-mail: catharine.whiteside{at}utoronto.ca

Abstract. In diabetes mellitus, enhanced activity of mesangial cell protein kinase C (PKC) may contribute to nephropathy. The purpose of this study was to determine whether high glucose alters mesangial cell diacylglycerol-sensitive PKC-, -ß₂, -, and - content, cellular distribution, and activity through polyol pathway activation. Primary cultured rat mesangial cells (passage 10) were growth-arrested in 0.5% fetal bovine serum and cultured in 5.6 mM glucose (NG) or 30 mM glucose (HG) for 48 h, with or without the aldose reductase inhibitor tolrestat or ARI-509. PKC isoform content in total cell lysates, or cytosol, membrane (Triton X-soluble), and particulate (sodium dodecyl sulfate-soluble) fractions was analyzed by immunoblotting, and band density in HG was expressed as a percentage of corresponding NG values. In HG at 48 h, increased total PKC- (222 ± 17% of NG, P < 0.001), -ß₂ (209 ± 12%, P < 0.001), and - (195 ± 19%, P < 0.001) were observed. L-Glucose had no effect on total PKC isoform content. HG caused increased membrane- and particulate-associated PKC- (257 ± 87 and 327 ± 66%, respectively, P < 0.05), membrane-associated PKC- (143 ± 10%, P < 0.05), and membrane-associated PKC- (186 ± 11%, P < 0.001), with no change in cytosol contents. The HG effects were not mimicked by L-glucose. In NG or HG, PKC-ß₂ was not detected in the cytosol fraction, and membrane and particulate association were unchanged with phorbol ester stimulation. Confocal immunofluorescence imaging revealed that in HG, PKC-, -, and - translocate to the nucleus and plasma membrane. Total PKC activity measured by in situ ³²P-phosphorylation of the epidermal growth factor receptor substrate increased from 18 ± 1 pmol/min per mg cell protein in NG to 33 ± 3 pmol/min per mg cell protein in HG (P < 0.002 versus NG). In NG, tolrestat and ARI-509 exposure caused increased PKC activity, enhanced accumulation of total PKC- and -ß₂, with no change in total or fractional recovery of PKC- or -. In HG, tolrestat and ARI-509 prevented the increase in total PKC- and membrane-associated PKC- and -. It is concluded that within 48 h of HG, enhanced mesangial cell PKC activity is associated with accumulation and cellular redistribution of diacylglycerol-sensitive PKC isoforms, and that increased PKC- content and membrane-associated PKC- and - are dependent on polyol pathway activation.

This article has been cited by other articles:

				W.-Y. So, Y. Wang, M. C.Y. Ng, X. Yang, R. C.W. Ma, V. Lam, A. P.S. Kong, P. C.Y. Tong, and J. C.N. Chan Aldose Reductase Genotypes and Cardiorenal Complications: An 8-year prospective analysis of 1,074 type 2 diabetic patients Diabetes Care, November 1, 2008; 31(11): 2148 - 2153. [Abstract] [Full Text] [PDF]

				L. Xia, H. Wang, S. Munk, H. Frecker, H. J. Goldberg, I. G. Fantus, and C. I. Whiteside Reactive oxygen species, PKC-beta1, and PKC-{zeta} mediate high-glucose-induced vascular endothelial growth factor expression in mesangial cells Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1280 - E1288. [Abstract] [Full Text] [PDF]

				M. Meier, J. Menne, J.-K. Park, and H. Haller Nailing down PKC isoform specificity in diabetic nephropathy two's company, three's a crowd Nephrol. Dial. Transplant., September 1, 2007; 22(9): 2421 - 2425. [Full Text] [PDF]

				F. Furlong, J. Crean, L. Thornton, R. O'Leary, M. Murphy, and F. Martin Dysregulated intracellular signaling impairs CTGF-stimulated responses in human mesangial cells exposed to high extracellular glucose Am J Physiol Renal Physiol, June 1, 2007; 292(6): F1691 - F1700. [Abstract] [Full Text] [PDF]

				M. Meier, J. Menne, J.-K. Park, M. Holtz, F. Gueler, T. Kirsch, M. Schiffer, M. Mengel, C. Lindschau, M. Leitges, et al. Deletion of Protein Kinase C-{varepsilon} Signaling Pathway Induces Glomerulosclerosis and Tubulointerstitial Fibrosis In Vivo J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1190 - 1198. [Abstract] [Full Text] [PDF]

				M. Meier, J.-K. Park, D. Overheu, T. Kirsch, C. Lindschau, F. Gueler, M. Leitges, J. Menne, and H. Haller Deletion of Protein Kinase C-{beta} Isoform In Vivo Reduces Renal Hypertrophy but Not Albuminuria in the Streptozotocin-Induced Diabetic Mouse Model Diabetes, February 1, 2007; 56(2): 346 - 354. [Abstract] [Full Text] [PDF]

				M. B. Marrero, A. K. Banes-Berceli, D. M. Stern, and D. C. Eaton Role of the JAK/STAT signaling pathway in diabetic nephropathy Am J Physiol Renal Physiol, April 1, 2006; 290(4): F762 - F768. [Abstract] [Full Text] [PDF]

				H. Frecker, S. Munk, H. Wang, and C. Whiteside Mesangial cell-reduced Ca2+ signaling in high glucose is due to inactivation of phospholipase C-{beta}3 by protein kinase C Am J Physiol Renal Physiol, November 1, 2005; 289(5): F1078 - F1087. [Abstract] [Full Text] [PDF]

				B. F. Schrijvers, A. S. De Vriese, and A. Flyvbjerg From Hyperglycemia to Diabetic Kidney Disease: The Role of Metabolic, Hemodynamic, Intracellular Factors and Growth Factors/Cytokines Endocr. Rev., December 1, 2004; 25(6): 971 - 1010. [Abstract] [Full Text] [PDF]

				H. Hua, S. Munk, H. Goldberg, I. G. Fantus, and C. I. Whiteside High Glucose-suppressed Endothelin-1 Ca2+ Signaling via NADPH Oxidase and Diacylglycerol-sensitive Protein Kinase C Isozymes in Mesangial Cells J. Biol. Chem., September 5, 2003; 278(36): 33951 - 33962. [Abstract] [Full Text] [PDF]

				S. Shaw, X. Wang, H. Redd, G. D. Alexander, C. M. Isales, and M. B. Marrero High Glucose Augments the Angiotensin II-induced Activation of JAK2 in Vascular Smooth Muscle Cells via the Polyol Pathway J. Biol. Chem., August 15, 2003; 278(33): 30634 - 30641. [Abstract] [Full Text] [PDF]

				I. Talior, M. Yarkoni, N. Bashan, and H. Eldar-Finkelman Increased glucose uptake promotes oxidative stress and PKC-{delta} activation in adipocytes of obese, insulin-resistant mice Am J Physiol Endocrinol Metab, August 1, 2003; 285(2): E295 - E302. [Abstract] [Full Text] [PDF]

				M. Haneda, D. Koya, M. Isono, and R. Kikkawa Overview of Glucose Signaling in Mesangial Cells in Diabetic Nephropathy J. Am. Soc. Nephrol., May 1, 2003; 14(5): 1374 - 1382. [Full Text] [PDF]

				G. T. Lee, H. Ha, M. Jung, H. Li, S. W. Hong, B. S. Cha, H. Chul Lee, and a. Y. Dong Cho Delayed Treatment with Lithospermate B Attenuates Experimental Diabetic Renal Injury J. Am. Soc. Nephrol., March 1, 2003; 14(3): 709 - 720. [Abstract] [Full Text] [PDF]

				D. J. Kelly, Y. Zhang, C. Hepper, R. M. Gow, K. Jaworski, B. E. Kemp, J. L. Wilkinson-Berka, and R. E. Gilbert Protein Kinase C {beta} Inhibition Attenuates the Progression of Experimental Diabetic Nephropathy in the Presence of Continued Hypertension Diabetes, February 1, 2003; 52(2): 512 - 518. [Abstract] [Full Text] [PDF]

				X. Wang, S. Shaw, F. Amiri, D. C. Eaton, and M. B. Marrero Inhibition of the JAK/STAT Signaling Pathway Prevents the High Glucose-Induced Increase in TGF-{beta} and Fibronectin Synthesis in Mesangial Cells Diabetes, December 1, 2002; 51(12): 3505 - 3509. [Abstract] [Full Text] [PDF]

				C. I. Whiteside and J. A. Dlugosz Mesangial cell protein kinase C isozyme activation in the diabetic milieu Am J Physiol Renal Physiol, June 1, 2002; 282(6): F975 - F980. [Abstract] [Full Text] [PDF]

				E. Tsiani, P. Lekas, I. G. Fantus, J. Dlugosz, and C. Whiteside High glucose-enhanced activation of mesangial cell p38 MAPK by ET-1, ANG II, and platelet-derived growth factor Am J Physiol Endocrinol Metab, January 1, 2002; 282(1): E161 - E169. [Abstract] [Full Text] [PDF]

				A. Kumar, K. S. Hawkins, M. A. Hannan, and M. B. Ganz Activation of PKC-beta I in glomerular mesangial cells is associated with specific NF-kappa B subunit translocation Am J Physiol Renal Physiol, October 1, 2001; 281(4): F613 - F619. [Abstract] [Full Text] [PDF]

				H. Hua, H. J. Goldberg, I.G. Fantus, and C. I. Whiteside High Glucose-Enhanced Mesangial Cell Extracellular Signal-Regulated Protein Kinase Activation and {alpha}1(IV) Collagen Expression in Response to Endothelin-1: Role of Specific Protein Kinase C Isozymes Diabetes, October 1, 2001; 50(10): 2376 - 2383. [Abstract] [Full Text]

				J. A. Dlugosz, S. Munk, J. Kapor-Drezgic, H. J. Goldberg, I. G. Fantus, J. W. Scholey, and C. I. Whiteside Stretch-induced mesangial cell ERK1/ERK2 activation is enhanced in high glucose by decreased dephosphorylation Am J Physiol Renal Physiol, October 1, 2000; 279(4): F688 - F697. [Abstract] [Full Text] [PDF]

				J. P. Godbout, J. Pesavento, M. E. Hartman, S. R. Manson, and G. G. Freund Methylglyoxal Enhances Cisplatin-induced Cytotoxicity by Activating Protein Kinase Cdelta J. Biol. Chem., January 18, 2002; 277(4): 2554 - 2561. [Abstract] [Full Text] [PDF]

				J. A. Dlugosz, S. Munk, E. Ispanovic, H. J. Goldberg, and C. I. Whiteside Mesangial cell filamentous actin disassembly and hypocontractility in high glucose are mediated by PKC-zeta Am J Physiol Renal Physiol, January 1, 2002; 282(1): F151 - F163. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673