Inhibition of p38 mitogen-activated protein kinases attenuates renal interstitial fibrosis in a murine unilateral ureteral occlusion model.

AIMS: Cellular hypoxia has been proposed as a major factor contributing to the pathogenesis of chronic renal injury. Much of our understanding of how mitogen-activated protein kinases (MAPK) signaling promotes renal fibrosis has been based on cell culture studies. Therefore, we used the unilateral ureteral occlusion (UUO) model to further elucidate the role of the p38 MAPK pathway in renal interstitial fibrosis induced by hypoxia.

MATERIALS AND METHODS: In the present study, 24 male mice were randomized into the following three groups (n=8 each): Sham group (DMSO solution), UUO group (UUO+DMSO solution) and UP group (UUO+p38 inhibitor). The model of UUO was conducted using an established procedure described previously. Histological changes in renal tubular interstitium were observed with hematoxylin-eosin (HE) and Masson's trichrome. The protein levels of hypoxia inducible factor-1α (HIF-1α)、transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF) and collagen type I were analyzed by western blotting and immunohistochemistry at 2weeks.

KEY FINDINGS: Increased expression of hypoxia inducible factor-1α (HIF-1α) in UUO mice confirmed the existence of hypoxia in renal interstitial. Hypoxia result in tubulointerstitial fibrosis via the molecular activation of connective tissue growth factor (CTGF). p38 inhibitor administration markedly downregulates the protein of connective tissue growth factor (CTGF) and collagen type I expression induced by hypoxia.

SIGNIFICANCE: An increase in p38 MAPK activation is induced by hypoxia. The hypoxia up-regulates the protein connective tissue growth factor (CTGF) and collagen I expression in a p38-dependent manner.