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

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. 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. 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. 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.

Gao F ，Wang Y ，Li S ，Wang Z ，Liu C ，Sun D ... -  《-》

Rhubarb and Astragalus Capsule Attenuates Renal Interstitial Fibrosis in Rats with Unilateral Ureteral Obstruction by Alleviating Apoptosis through Regulating Transforming Growth Factor beta1 (TGF-β1)/p38 Mitogen-Activated Protein Kinases (p38 MAPK) Pathw

Zeng X ，Cai G ，Liang T ，Li Q ，Yang Y ，Zhong X ，Zou X ，Qin M ，Mi Z ... -  《MEDICAL SCIENCE MONITOR》

Transplantation of endothelial progenitor cells alleviates renal interstitial fibrosis in a mouse model of unilateral ureteral obstruction.

Ma YY ，Sun D ，Li J ，Yin ZC ... -  《-》

Ribes diacanthum Pall (RDP) ameliorates UUO-induced renal fibrosis via both canonical and non-canonical TGF-β signaling pathways in mice.

Ribes diacanthum Pall (RDP), a folk medicine, has been widely used in Mongolia to treat urinary system diseases. To investigate the effectiveness of RDP on unilateral ureteral obstruction (UUO)-induced renal interstitial fibrosis and the underlying mechanisms. A total of 60 mice were randomly divided into six groups: sham group, sham plus RDP (40 mg/kg) group, UUO model group, and UUO model plus RDP (10, 20 or 40 mg/kg) groups. After surgery, aqueous extract of RDP were administrated intragastrically (i.g) daily for a week and ipsilateral kidneys were collected seven days after surgery. Levels of blood urea nitrogen (BUN) and serum creatinine (Scr) were detected to reflect the kidney injury. Hematoxylin & eosin and Masson's trichrome staining were used to evaluate the kidney morphological changes and fibrosis, respectively. ELISA was used to examine the levels of pro-inflammatory cytokines. Immunohistochemistry, western blot and PCR were used to examine the expression levels of key proteins involved in transforming growth factor (TGF-β)/Smad and mitogen-activated protein kinase (MAPK) signaling pathways. RDP treatment attenuates the level of BUN and kidney fibrosis in UUO mice, decreases the expressions of interleukin-6, tumor necrosis factor-α, Interleukin-1α, TGF-β1, monocyte chemotactic protein-1, α-smooth muscle actin, collagen I, fibronectin, and vimentin, while increases the expressions of E-cadherin and hepatocyte growth factor. Moreover, RDP administration significantly decreases the levels of p-Smad2/3, p-ERK1/2, p-p38 and p-JNK, while increases the expression level of Smad7 in UUO models. These data demonstrate that RDP ameliorates renal fibrosis through TGF-β/Smad and MAPK pathways in a UUO mouse model.

Gu L ，Wang Y ，Yang G ，Tilyek A ，Zhang C ，Li S ，Yu B ，Chai C ，Cao Z ... -  《-》

Piceatannol Attenuates Renal Fibrosis Induced by Unilateral Ureteral Obstruction via Downregulation of Histone Deacetylase 4/5 or p38-MAPK Signaling.

Choi SY ，Piao ZH ，Jin L ，Kim JH ，Kim GR ，Ryu Y ，Lin MQ ，Kim HS ，Kee HJ ，Jeong MH ... -  《PLoS One》