| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
* To whom correspondence should be addressed. E-mail: tomoko.takano{at}mcgill.ca.
In the passive Heymann nephritis (PHN) model of rat membranous nephropathy, complement C5b-9 causes sublytic injury of glomerular epithelial cells (GEC). We have previously shown that sublytic concentration of C5b-9 triggers a variety of biological events in GEC. In the current study, we demonstrate that complement activates p38 mitogen-activated protein kinase (MAPK) in GEC and address the role of p38 in complement-mediated cell injury. When cultured rat GEC were stimulated with complement, p38 kinase activity and phosphorylation were increased by ~2.4 fold, as compared with control. Treatment with p38 inhibitors significantly augmented complement-mediated cytotoxicity. In contrast, when the constitutively active mutant of transforming growth factor-
-activated kinase 1 (TAK1), a kinase upstream of p38, was expressed in GEC in an inducible manner, cytotoxicity was significantly reduced, as compared with uninduced cells. p38 inhibitors abolished the protective effect of TAK1 expression. By analogy to cultured cells, p38 activity was also increased in glomeruli from rats with PHN and treatment with the p38 inhibitor FR167653 increased proteinuria. Complement induced phosphorylation of MAPK-associated protein kinase-2 (MAPKAP-2), a kinase downstream of p38 in GEC. HSP27 is a cytoskeleton-interacting substrate of MAPKAP-2. Overexpression of the wild type HSP27, but not a non-phosphorylatable mutant, markedly reduced complement-mediated GEC injury. In summary, complement activates p38 MAPK in GEC in vitro and in glomeruli of rats with PHN. The activation of p38 MAPK appears to be cytoprotective for GEC against complement-mediated GEC injury. Phosphorylation of HSP27 may mediate this cytoprotection.
This article has been cited by other articles:
|
|
 |
|
  A. V. Cybulsky, T. Takano, J. Guillemette, J. Papillon, R. A. Volpini, and J. A. Di Battista The Ste20-like kinase SLK promotes p53 transactivation and apoptosis Am J Physiol Renal Physiol, October 1, 2009; 297(4): F971 - F980. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-T. Hsu, W.-H. Kan, C.-H. Hsieh, M. A. Choudhry, M. G. Schwacha, K. I. Bland, and I. H. Chaudry Mechanism of estrogen-mediated intestinal protection following trauma-hemorrhage: p38 MAPK-dependent upregulation of HO-1 Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2008; 294(6): R1825 - R1831. [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]
|
|
|
|
|
|
H. Zhang, A. V. Cybulsky, L. Aoudjit, J. Zhu, H. Li, N. Lamarche-Vane, and T. Takano Role of Rho-GTPases in complement-mediated glomerular epithelial cell injury Am J Physiol Renal Physiol, July 1, 2007; 293(1): F148 - F156. [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]
|
|
|
|
|
|
L. Aoudjit, A. Potapov, and T. Takano Prostaglandin E2 promotes cell survival of glomerular epithelial cells via the EP4 receptor Am J Physiol Renal Physiol, June 1, 2006; 290(6): F1534 - F1542. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Maulik Effect of p38 MAP kinase on cellular events during ischemia and reperfusion: possible therapy Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2302 - H2303. [Full Text] [PDF]
|
|
|
|
|
|
T. Okada, H. Otani, Y. Wu, S. Kyoi, C. Enoki, H. Fujiwara, T. Sumida, R. Hattori, and H. Imamura Role of F-actin organization in p38 MAP kinase-mediated apoptosis and necrosis in neonatal rat cardiomyocytes subjected to simulated ischemia and reoxygenation Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2310 - H2318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Cybulsky, R. J. Quigg, and D. J. Salant Experimental membranous nephropathy redux Am J Physiol Renal Physiol, October 1, 2005; 289(4): F660 - F671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Koshikawa, M. Mukoyama, K. Mori, T. Suganami, K. Sawai, T. Yoshioka, T. Nagae, H. Yokoi, H. Kawachi, F. Shimizu, et al. Role of p38 Mitogen-Activated Protein Kinase Activation in Podocyte Injury and Proteinuria in Experimental Nephrotic Syndrome J. Am. Soc. Nephrol., September 1, 2005; 16(9): 2690 - 2701. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Cybulsky, T. Takano, J. Papillon, K. Bijian, and J. Guillemette Activation of the extracellular signal-regulated kinase by complement C5b-9 Am J Physiol Renal Physiol, September 1, 2005; 289(3): F593 - F603. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
