Abstract
The accumulation of fibroblasts is a critical step in the development of fibrosis, and lysophosphatidic acid (LPA) promotes fibrosis by regulating multiple fibroblast functions. Autotaxin (ATX) is a key LPA-producing enzyme, and we hypothesized that ATX contributes to the development of renal interstitial fibrosis through LPA-mediated effects on fibroblast functions. In a mouse model of renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO), the levels of renal ATX protein and activity increased with the progression of fibrosis in ligated kidneys, despite concurrent reductions in renal ATX mRNA. UUO enhanced vascular permeability in the renal interstitium, and ATX protein localized to areas of vascular leak, suggesting that vascular leak allowed ATX to enter the renal interstitium. In vitro studies showed that ATX induces the migration and proliferation of renal fibroblasts and enhances the vascular permeability of endothelial monolayers. Finally, pharmacological inhibition of ATX partially attenuated renal interstitial fibrosis. These results suggest that during the development of renal fibrosis, ATX accumulates in the renal interstitium and drives fibroblast accumulation and promotes renal interstitial vascular leak, thereby partially contributing to the pathogenesis of renal interstitial fibrosis. Taken together, ATX inhibition may have the potential to be a novel therapeutic strategy to combat renal interstitial fibrosis.
Highlights
The accumulation of fibroblasts is a critical step in the development of fibrosis, and lysophosphatidic acid (LPA) promotes fibrosis by regulating multiple fibroblast functions
Progressive renal interstitial fibrosis was induced by ureteral ligation, as demonstrated by increases in Mallory-Azan staining of renal collagen (Fig. 1a) and renal mRNA levels of COLIα1 (Fig. 1b)
Renal ATX protein and activity levels increase with progression of renal interstitial fibrosis, and pharmacological antagonism of ATX reduces the accumulation of fibroblasts in ligated kidneys and partially protects mice from renal interstitial fibrosis in the ureteral obstruction (UUO) model
Summary
The accumulation of fibroblasts is a critical step in the development of fibrosis, and lysophosphatidic acid (LPA) promotes fibrosis by regulating multiple fibroblast functions. Pharmacological inhibition of ATX partially attenuated renal interstitial fibrosis These results suggest that during the development of renal fibrosis, ATX accumulates in the renal interstitium and drives fibroblast accumulation and promotes renal interstitial vascular leak, thereby partially contributing to the pathogenesis of renal interstitial fibrosis. Increased LPA concentrations have been reported in biological fluids sampled from organs developing fibrosis, such as bronchoalveolar lavage fluid recovered from the lungs of patients with idiopathic pulmonary fibrosis, or from mice in the bleomycin model of pulmonary fibrosis[9]. These findings suggest that LPA may play a www.nature.com/scientificreports/. Whether ATX contributes to the pathogenesis of renal interstitial fibrosis has yet to be investigated
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