| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425; and
Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 60637
In glomerular diseases of diverse etiologies, dysfunction of the glomerular barrier to protein passage results in proteinuria, and proteinuria is considered an independent risk factor that plays a direct role in inflammation, interstitial fibrosis, and renal failure. The mechanism by which proteinuria leads to nephrotoxic injury is unclear, but a role for complement in mediating interstitial damage appears likely. We describe a strategy for Ag-specific targeting of complement inhibitors using a single chain Ab fragment and show that complement inhibitors targeted to the tubular epithelium protect against tubulointerstitial injury and renal dysfunction in a rat model of puromycin-induced nephrosis. The targeting of systemically administered complement inhibitors markedly enhanced their efficacy and obviated the need to systemically inhibit complement, thus reducing the risk of compromising host defense and immune homeostasis. Targeted inhibition of complement activation by Crry, and of membrane attack complex (MAC) formation by CD59 was equally therapeutic, demonstrating that the MAC plays a key role in proteinuria-induced tubulointerstitial injury. CD59 activity was dependent on its being targeted to the site of complement activation, and this is the first report of specific inhibition of the MAC in vivo after systemic administration of inhibitor. The data establish the MAC is a valid target for pharmaceutical intervention in proteinuric disorders and provide an approach to investigate the role of the MAC in complement-dependent disease under clinically relevant conditions.
This article has been cited by other articles:
|
|
 |
|
  M. Naesens, L. Li, L. Ying, P. Sansanwal, T. K. Sigdel, S.-C. Hsieh, N. Kambham, E. Lerut, O. Salvatierra, A. J. Butte, et al. Expression of Complement Components Differs Between Kidney Allografts from Living and Deceased Donors J. Am. Soc. Nephrol., August 1, 2009; 20(8): 1839 - 1851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Tang, B. Lu, E. Hatch, S. H. Sacks, and N. S. Sheerin C3a Mediates Epithelial-to-Mesenchymal Transition in Proteinuric Nephropathy J. Am. Soc. Nephrol., March 1, 2009; 20(3): 593 - 603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Gaarkeuken, M. A. Siezenga, K. Zuidwijk, C. van Kooten, T. J. Rabelink, M. R. Daha, and S. P. Berger Complement activation by tubular cells is mediated by properdin binding Am J Physiol Renal Physiol, November 1, 2008; 295(5): F1397 - F1403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Abbate, C. Zoja, D. Corna, D. Rottoli, C. Zanchi, N. Azzollini, S. Tomasoni, S. Berlingeri, M. Noris, M. Morigi, et al. Complement-Mediated Dysfunction of Glomerular Filtration Barrier Accelerates Progressive Renal Injury J. Am. Soc. Nephrol., June 1, 2008; 19(6): 1158 - 1167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. S. Sheerin, P. Risley, K. Abe, Z. Tang, W. Wong, T. Lin, and S. H. Sacks Synthesis of complement protein C3 in the kidney is an important mediator of local tissue injury FASEB J, April 1, 2008; 22(4): 1065 - 1072. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Boor, K. Sebekova, T. Ostendorf, and J. Floege Treatment targets in renal fibrosis Nephrol. Dial. Transplant., December 1, 2007; 22(12): 3391 - 3407. [Full Text] [PDF]
|
|
|
|
|
|
M. Abbate, C. Zoja, and G. Remuzzi How Does Proteinuria Cause Progressive Renal Damage? J. Am. Soc. Nephrol., November 1, 2006; 17(11): 2974 - 2984. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Spitzer, X. Wu, X. Ma, L. Xu, K. P. Ponder, and J. P. Atkinson Cutting Edge: Treatment of Complement Regulatory Protein Deficiency by Retroviral In Vivo Gene Therapy J. Immunol., October 15, 2006; 177(8): 4953 - 4956. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Huang, F. Qiao, R. Abagyan, S. Hazard, and S. Tomlinson Defining the CD59-C9 Binding Interaction J. Biol. Chem., September 15, 2006; 281(37): 27398 - 27404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nangaku A Crry for polar shedding Nephrol. Dial. Transplant., July 1, 2006; 21(7): 1773 - 1775. [Full Text] [PDF]
|
|
|
|
|
|
P. Jha, J.-H. Sohn, Q. Xu, Y. Wang, H. J. Kaplan, P. S. Bora, and N. S. Bora Suppression of Complement Regulatory Proteins (CRPs) Exacerbates Experimental Autoimmune Anterior Uveitis (EAAU). J. Immunol., June 15, 2006; 176(12): 7221 - 7231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ostendorf, S. Rong, P. Boor, S. Wiedemann, U. Kunter, U. Haubold, C. R.C. van Roeyen, F. Eitner, H. Kawachi, G. Starling, et al. Antagonism of PDGF-D by Human Antibody CR002 Prevents Renal Scarring in Experimental Glomerulonephritis J. Am. Soc. Nephrol., April 1, 2006; 17(4): 1054 - 1062. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Thurman and V. M. Holers The Central Role of the Alternative Complement Pathway in Human Disease J. Immunol., February 1, 2006; 176(3): 1305 - 1310. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
