Lysyl Oxidase Expression and Collagen Cross-Linking during Chronic Adriamycin Nephropathy

Abstract

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 lysyl oxidase and the content in collagen crosslinks at various stages of chronic Adriamycin nephropathy in Sprague-Dawley rats. Lysyl oxidase expression was determined by RT-PCR; collagen pyridinium residues, indicating lysyl oxidase induced cross-links, were evaluated by HPLC. These parameters followed 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-treated and control rats, until diffuse interstitial fibrosis developed (16 weeks), showing at this time a 2- to 3-fold increment. Lysyl oxidase was expressed by several renal cell lines and in tubular-epithelial cells it was up-regulated in vitro by TGFβ-1, a recognized fibrogenetic factor in Adriamycin nephropathy. Our observations demonstrated that an increased expression of lysyl oxidase in the kidney precedes the development of diffuse fibrotic lesions and that, at this stage, collagenic structures contain highly cross-linked components, the final product of lysyl oxidase activity. The evidence of lysyl oxidase up-regulation in tubular epithelial cells by the same factor implicated in Adriamycin toxicity in the kidney suggests a common pathogenetic mechanism. Collagen cross-link formation by lysyl oxidase may be implicated in the pathogenesis of irreversible, fibrotic renal lesions.

Transforming growth factor-β1 mediated up-regulation of lysyl oxidase in the kidneys of hereditary nephrotic mouse with chronic renal fibrosis

“…However, in situ hybridization indicated that the LOX was mainly produced by renal tubular epithelial cells, not myofibroblasts, in the fibrotic kidneys of aged ICGN mice. Such a tubular epithelial cellspecific hyper-induction of LOX mRNA expression was consistent with a previous report on rat kidneys with adriamycin-induced nephropathy [6]. On the other hand, trace levels of LOX mRNA expressed in the glomeruli of ICGN mouse kidneys, but it seemed to be the same expression level with those of ICR mice (data not shown).…”

Influence of stress on extracellular matrix and integrin biology

“…On one hand, anti-cancer agents reduce the synthesis of some ECM components, including collagen, fibronectin or proteoglycan (Sasaki et al, 1987;Jikko et al, 1996;Muszynska et al, 2001). However, these agents stimulate lysyl oxidase and subsequent collagen polymerization (Di Donato et al, 1997). Moreover, drugs as well as ionizing radiations also induce the secretion of TGFb, a cytokine with potent pro-fibrotic action (Ise et al, 2004).…”

Lysyl Oxidase Activates the Transcription Activity of Human Collagene III Promoter

“…DISCUSSION LOX plays a critical role in the organization of extracellular matrix, stabilizing the molecules of collagen and elastin (1,(55)(56)(57). Because of that, LOX is considered one of the main actors in the development of many pathological fibrotic processes (5)(6)(7)(8). Also, LOX has been proposed as the tumor suppressor gene, because of its down-regulation in many experimental and naturally occurring tumors and its anti-ras activity (14,15,17,18,30,58).…”

“…Several reports have recently suggested a clear association between organ fibrosis and increased LOX activity. This has been described in several chronic human liver diseases (5), in rat experimental hepatic fibrosis (CCl 4 ) (6), in idiopathic and experimental lung fibrosis (7), in adriamycin-induced kidney fibrosis in rat (8), and in other pathologies resulting in fibrosis (9 -13).…”