LYSYL OXIDASE EXPRESSION AND COLLAGEN CROSS-LINKING DURING CHRONIC ADRIAMYCIN NEPHROPATHY

Collagen cross-linking induced by lysyl oxidase has been implicated in liver and lung fibrosis. To define the role of this process in kidney fibrosis, we investigated the renal expression of lyspl oxidase and t he content in collagen crosslinks at various stages of chronic Adriamy cin nephropathy in Sprague-Dawley rats, Lysyl oxidase expression was d etermined by RT-PCR; collagen pyridinium residues, indicating lysyl ox idase induced cross-links, were evaluated by HPLC. These parameters fo llow ed a synergic albeit asynchronous outcome: (a) lysyl oxidase mRNA levels in total kidney, glomeruli and medulla from Adriamycin-treated rats increased up to 3 times compared to controls between week 8 and 12, then returning within the normal range: (b) the pyridinium residue content did not show any significant difference between Adriamycin-tr eated and control rats, until diffuse interstitial fibrosis developed( 16 weeks), showing at this time a 2- to 3-fold increment. Lysyl oxidas e was expressed by several renal cell lines and in tubular-spithelial cells it was up-regulated in vitro by TGF beta-1, a recognized fibroge netic factor in Adriamycin nephropathy, Our observations demonstrated that an increased expression of lysyl oxidase in the kidney precedes t he development of diffuse fibrotic lesions and that, at this stage, co llagenic structures contain highly cross-linked components, the final product of lysyl oxidase activity, The evidence of lysyl oxidase up-re gulation in tubular epithelial cells by the same factor implicated in Adriamycin toxicity in the kidney suggests a common pathogenetic mecha nism, Collagen cross-link formation by lysyl oxidase may be implicated in the pathogenesis of irreversible, fibrotic renal lesions.