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Functional Relevance of Activated ß1 Integrins in Mercury-Induced Nephritis

ESTHER ESCUDERO^*, ANA MARTÍN^*, MARTA NIETO, ELENA NIETO^*, ELENA NAVARRO^*, ALFONSO LUQUE, CARLOS CABAÑAS, FRANCISCO SÁNCHEZ-MADRID and FRANCISCO MAMPASO^*

^* Department of Pathology, Hospital Ramón y Cajal, Universidad de Alcalá, Madrid, Spain.
Immunology Section, Hospital de la Princesa, Universidad Autónoma, Madrid, Spain.
Department of Biochemistry, Medical School, Universidad Complutense, Madrid, Spain.

Correspondence to Dr. Francisco Mampaso, Pathology Department, Hospital Ramón y Cajal, Carretera Colmenar km 9.100, 28034 Madrid, Spain. Phone: +91 336 8052; Fax: +91 336 9016; E-mail: fmampaso{at}hrc.insalud.es

Abstract. Cell adhesion through different adhesion molecules is a crucial event in the inflammatory response. Integrins can only bind and mediate cellular adhesion after their activation by different specific stimuli. The state of ß1 integrin activation can be assessed by a group of monoclonal antibodies (HUTS) that selectively recognize ß1 integrins in their active form. A similar activated epitope in the rat was defined using the anti-human monoclonal antibody HUTS-21, which recognizes an activation-dependent epitope on the ß1 chain. It was found that the divalent cations Mn²⁺ and Hg²⁺ were able to induce in vitro the activation of ß1 integrins on rat lymphocytes. The Hg²⁺ cation induces an autoimmune disease in the Brown Norway rat characterized by synthesis and glomerular deposits of anti-glomerular basement membrane antibodies, proteinuria, and interstitial nephritis. Using the mercury model of nephritis, it was found that the expression of HUTS-21 epitope is induced in vivo in rat lymphocytes, and its appearance is correlated with the other parameters at the onset of the disease. In addition, the administration of HUTS-21 monoclonal antibody to HgCl₂-treated rats offered evidence of its protective effects (1) against infiltration of renal interstitium by leukocytes, and (2) in the reduction of anti-glomerular basement membrane synthesis and glomerular deposition. Nevertheless, urinary protein values remained unaffected. These results demonstrate a key role of ß1-activated integrins in both leukocyte cell-cell interactions and leukocyte infiltration pathway mechanism, and also indicate that leukocyte migration may have less importance in the development of this disease than previously thought.

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				A. Molina, M. Ubeda, M. M. Escribese, L. Garcia-Bermejo, D. Sancho, G. P. de Lema, F. Liano, C. Cabanas, F. Sanchez-Madrid, and F. Mampaso Renal Ischemia/Reperfusion Injury: Functional Tissue Preservation by Anti-Activated {beta}1 Integrin Therapy J. Am. Soc. Nephrol., February 1, 2005; 16(2): 374 - 382. [Abstract] [Full Text] [PDF]

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