Linked Life Data

15843577

Source:http://linkedlifedata.com/resource/pubmed/id/15843577

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2005-4-21
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0022-1767
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
174
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5750-7
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:15843577-Animals, pubmed-meshheading:15843577-Antigens, CD59, pubmed-meshheading:15843577-Antigens, Surface, pubmed-meshheading:15843577-Complement Inactivator Proteins, pubmed-meshheading:15843577-Complement Membrane Attack Complex, pubmed-meshheading:15843577-Disease Models, Animal, pubmed-meshheading:15843577-Drug Delivery Systems, pubmed-meshheading:15843577-Female, pubmed-meshheading:15843577-Kidney Tubules, Proximal, pubmed-meshheading:15843577-Nephritis, Interstitial, pubmed-meshheading:15843577-Nephrotic Syndrome, pubmed-meshheading:15843577-Organ Specificity, pubmed-meshheading:15843577-Rats, pubmed-meshheading:15843577-Rats, Sprague-Dawley, pubmed-meshheading:15843577-Receptors, Cell Surface, pubmed-meshheading:15843577-Receptors, Complement, pubmed-meshheading:15843577-Recombinant Proteins
pubmed:year
2005
pubmed:articleTitle
Complement inhibitors targeted to the proximal tubule prevent injury in experimental nephrotic syndrome and demonstrate a key role for C5b-9.
pubmed:affiliation
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural