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) All Versions of this Article: ASN.2004121084v1 16/9/2690    most recent 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 Koshikawa, M. Articles by Nakao, K. Search for Related Content PubMed PubMed Citation Articles by Koshikawa, M. Articles by Nakao, K.

Role of p38 Mitogen-Activated Protein Kinase Activation in Podocyte Injury and Proteinuria in Experimental Nephrotic Syndrome

Masao Koshikawa^*, Masashi Mukoyama^*, Kiyoshi Mori^*, Takayoshi Suganami^*, Kazutomo Sawai^*, Tetsuro Yoshioka^*, Tetsuya Nagae^*, Hideki Yokoi^*, Hiroshi Kawachi, Fujio Shimizu, Akira Sugawara^* and Kazuwa Nakao^*

^* Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, and Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Address correspondence to: Dr. Masashi Mukoyama, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Phone: +81-75-751-4285; Fax: +81-75-771-9452; E-mail: muko{at}kuhp.kyoto-u.ac.jp

Received for publication December 14, 2004. Accepted for publication May 31, 2005.

Podocytes play an important role in maintaining normal glomerular function and structure, and podocyte injury leads to proteinuria and glomerulosclerosis. The family of mitogen-activated protein kinases (MAPK; extracellular signal-regulated kinase [ERK], c-Jun N-terminal kinase, and p38) may be implicated in the progression of various glomerulopathies, but the role of MAPK in podocyte injury remains elusive. This study examined phosphorylation of p38 MAPK in clinical glomerulopathies with podocyte injury, as well as in rat puromycin aminonucleoside (PAN) nephropathy and mouse adriamycin (ADR) nephropathy. The effect of treatment with FR167653, an inhibitor of p38 MAPK, was also investigated in rodent models. In human podocyte injury diseases, the increased phosphorylation of p38 MAPK was observed at podocytes. In PAN and ADR nephropathy, the phosphorylation of p38 MAPK and ERK was marked but transient, preceding overt proteinuria. Pretreatment with FR167653 (day –2 to day 14, subcutaneously) to PAN or ADR nephropathy completely inhibited p38 MAPK activation and attenuated ERK phosphorylation, with complete suppression of proteinuria. Electron microscopy and immunohistochemistry for nephrin and connexin43 revealed that podocyte injury was markedly ameliorated by FR167653. Furthermore, early treatment with FR167653 effectively prevented glomerulosclerosis and renal dysfunction in the chronic phase of ADR nephropathy. In cultured podocytes, PAN or oxidative stress induced the phosphorylation of p38 MAPK along with actin reorganization, and FR167653 inhibited such changes. These findings indicate that the activation of MAPK is necessary for podocyte injury, suggesting that p38 MAPK and, possibly, ERK should become a potential target for therapeutic intervention in proteinuric glomerulopathies.

This article has been cited by other articles:

				D.-S. Jung, J. J. Li, S.-J. Kwak, S. H. Lee, J. Park, Y. S. Song, T.-H. Yoo, S. H. Han, J. E. Lee, D. K. Kim, et al. FR167653 inhibits fibronectin expression and apoptosis in diabetic glomeruli and in high-glucose-stimulated mesangial cells Am J Physiol Renal Physiol, August 1, 2008; 295(2): F595 - F604. [Abstract] [Full Text] [PDF]

				J. Guo, R. Ananthakrishnan, W. Qu, Y. Lu, N. Reiniger, S. Zeng, W. Ma, R. Rosario, S. F. Yan, R. Ramasamy, et al. RAGE Mediates Podocyte Injury in Adriamycin-induced Glomerulosclerosis J. Am. Soc. Nephrol., May 1, 2008; 19(5): 961 - 972. [Abstract] [Full Text] [PDF]

				Y. Harita, H. Kurihara, H. Kosako, T. Tezuka, T. Sekine, T. Igarashi, and S. Hattori Neph1, a Component of the Kidney Slit Diaphragm, Is Tyrosine-phosphorylated by the Src Family Tyrosine Kinase and Modulates Intracellular Signaling by Binding to Grb2 J. Biol. Chem., April 4, 2008; 283(14): 9177 - 9186. [Abstract] [Full Text] [PDF]

				F. Y. Ma, G. H. Tesch, R. A. Flavell, R. J. Davis, and D. J. Nikolic-Paterson MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1556 - F1563. [Abstract] [Full Text] [PDF]

				K. Sawai, M. Mukoyama, K. Mori, M. Kasahara, M. Koshikawa, H. Yokoi, T. Yoshioka, Y. Ogawa, A. Sugawara, H. Nishiyama, et al. Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1363 - F1372. [Abstract] [Full Text] [PDF]

				G. R. Reddy, M. J. Pushpanathan, R. F. Ransom, L. B. Holzman, F. C. Brosius III, M. Diakonova, P. Mathieson, M. A. Saleem, E. O. List, J. J. Kopchick, et al. Identification of the Glomerular Podocyte as a Target for Growth Hormone Action Endocrinology, May 1, 2007; 148(5): 2045 - 2055. [Abstract] [Full Text] [PDF]

				A. Sheryanna, G. Bhangal, J. McDaid, J. Smith, A. Manning, B. M.J. Foxwell, M. Feldmann, H. T. Cook, C. D. Pusey, and F. W.K. Tam Inhibition of p38 Mitogen-Activated Protein Kinase Is Effective in the Treatment of Experimental Crescentic Glomerulonephritis and Suppresses Monocyte Chemoattractant Protein-1 but Not IL-1beta or IL-6 J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1167 - 1179. [Abstract] [Full Text] [PDF]

				K. Y. Jung, K. Chen, M. Kretzler, and C. Wu TGF-beta1 Regulates the PINCH-1-Integrin-Linked Kinase-{alpha}-Parvin Complex in Glomerular Cells J. Am. Soc. Nephrol., January 1, 2007; 18(1): 66 - 73. [Abstract] [Full Text] [PDF]

				J. Li, N. V. Campanale, R. J. Liang, J. A. Deane, J. F. Bertram, and S. D. Ricardo Inhibition of p38 Mitogen-Activated Protein Kinase and Transforming Growth Factor-{beta}1/Smad Signaling Pathways Modulates the Development of Fibrosis in Adriamycin-Induced Nephropathy Am. J. Pathol., November 1, 2006; 169(5): 1527 - 1540. [Abstract] [Full Text] [PDF]

				J. Prakash, M. Sandovici, V. Saluja, M. Lacombe, R. Q. J. Schaapveld, M. H. de Borst, H. van Goor, R. H. Henning, J. H. Proost, F. Moolenaar, et al. Intracellular Delivery of the p38 Mitogen-Activated Protein Kinase Inhibitor SB202190 [4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole] in Renal Tubular Cells: A Novel Strategy to Treat Renal Fibrosis J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 8 - 19. [Abstract] [Full Text] [PDF]

				J. Li, J. A. Deane, N. V. Campanale, J. F. Bertram, and S. D. Ricardo Blockade of p38 Mitogen-Activated Protein Kinase and TGF-beta1/Smad Signaling Pathways Rescues Bone Marrow-Derived Peritubular Capillary Endothelial Cells in Adriamycin-Induced Nephrosis J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2799 - 2811. [Abstract] [Full Text] [PDF]

				C. Herve and J. Dantal Possible new perspectives for our understanding of nephrotic syndrome recurrence Nephrol. Dial. Transplant., January 1, 2006; 21(1): 10 - 13. [Full Text] [PDF]

				K. Susztak, A. C. Raff, M. Schiffer, and E. P. Bottinger Glucose-Induced Reactive Oxygen Species Cause Apoptosis of Podocytes and Podocyte Depletion at the Onset of Diabetic Nephropathy Diabetes, January 1, 2006; 55(1): 225 - 233. [Abstract] [Full Text] [PDF]

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