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Differential Regulation of Soluble Guanylyl Cyclase Expression and Signaling by Collagens: Involvement of Integrin-Linked Kinase

Sergio De Frutos^*,, Marta Saura^*,, Mercedes Griera^*,, Francisco Javier Rivero-Vilches^*,, Carlos Zaragoza, Diego Rodriguez-Puyol^, and Manuel Rodriguez-Puyol^*,

^* Physiology Department, Alcalá University, "Reina Sofia" Institute for Nephrologic Research, National Center for Cardiovascular Research (CNIC), and Nephrology Division, "Príncipe de Asturias" Hospital, Alcalá de Henares, Madrid, Spain

Address correspondence to: Dr. Manuel Rodriguez Puyol, Departamento de Fisiología, Facultad de Medicina, Universidad de Alcalá, Crta. Madrid-Barcelona Km 33, 600 Alcalá de Henares, 28871 Madrid, Spain. Phone: 34-91-885-4551; Fax: 34-91-885-4590; E-mail: manuel.rodriguez{at}uah.es

Received for publication July 23, 2004. Accepted for publication June 8, 2005.

Glomerular diseases are characterized by an abnormal synthesis of extracellular matrix proteins, such as collagen type I. Evidence that growth on collagen type I downregulates soluble guanylyl cyclase (sGC) expression and the responsiveness of human mesangial cells to nitric oxide (NO) by activating specific integrin signals involving integrin-linked kinase (ILK) is presented. Human mesangial cells were grown on collagen type I or IV for 24 to 72 h. Compared with collagen IV, growth on collagen I reduced the protein expression and NO-stimulated enzyme activity of sGC. This downregulation was effected at the level of transcription, because steady-state sGC mRNA expression was reduced on collagen I, but inhibition of transcription with Actinomycin D revealed no differences in transcript stability between the two culture conditions. Collagen I also reduced the capacity of cells to relax in response to NO after H₂O₂ challenge and inhibited NO-induced phosphorylation of vasodilator-activated phosphoprotein, a target of cyclic guanine monophosphate–dependent protein kinase. Examination of the surface expression of integrins, the receptors for extracellular matrix components, revealed that 1 and 2 integrin subunits were more abundant on cells that were grown on collagen IV and that surface expression of 1 integrin did not vary with collagen type. However, growth on collagen I induced 1 integrin to adopt its active conformation, and this activation of 1 integrin was accompanied by increased activity of its downstream effector ILK. Dominant-negative suppression of ILK signaling relieved the suppression of sGC expression and NO-induced vasodilator-activated phosphoprotein phosphorylation induced by collagen I.

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