Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice

Abstract

Ruxolitinib is a selective inhibitor of Jak1/2. Downstream signaling pathways of Jak, such as Stat3 and Akt/mTOR, are overactivated and contribute to renal interstitial fibrosis. Therefore, we explored the effect of Ruxolitinib on this pathological process. Unilateral ureteral obstruction (UUO) models and TGF-β1-treated fibroblasts and renal tubular epithelial cells were adopted in this study. Ruxolitinib was administered to UUO mice and TGF-β1-treated cells. Kidneys from UUO mice with Ruxolitinib treatment displayed less tubular injuries compared with those without Ruxolitinib treatment. Ruxolitinib treatment suppressed fibroblast activation and extracellular matrix (ECM) production in UUO kidneys and TGF-β1-treated fibroblasts. Ruxolitinib treatment also blocked epithelial-mesenchymal transition (EMT) in UUO kidneys and TGF-β 1-treated renal tubular epithelial cells. Moreover, Ruxolitinib treatment alleviated UUO-induced inflammation, oxidative stress and apoptosis. Mechanistically, Ruxolitinib treatment attenuated activation of both Stat3 and Akt/mTOR/Yap pathways. In conclusion, Ruxolitinib treatment can ameliorate UUO-induced renal interstitial fibrosis, suggesting that Ruxolitinib may be potentially used to treat fibrotic kidney disease.

C-C Motif Chemokine Ligand-17 as a Novel Biomarker and Regulator of Epithelial Mesenchymal Transition in Renal Fibrogenesis

“…Evidence has shown that progressive worsening of renal function is associated with α-SMA positive interstitial myofibroblasts in diabetic and membranous nephropathy [ 5 , 6 ]. Studies have shown that substances that block the EMT by mediating inflammation, oxidative stress, and apoptosis in renal tissues can alleviate EMT-induced fibrogenesis [ 27 , 28 , 29 ]. Consistent with these studies, we observed that CCL17 modulated the phenotypic transformation of renal tubular epithelial cells to induce renal fibrosis as evidenced by the increased expression of α-SMA, vimentin, and collagen I.…”

Deciphering the Pharmacological Mechanisms of Taohe-Chengqi Decoction Extract Against Renal Fibrosis Through Integrating Network Pharmacology and Experimental Validation In Vitro and In Vivo

“…To further validate this postulation, we investigated the therapeutic effects of NE-THCQ on renal tubular epithelial cells in vitro and unilateral ureteral obstruction (UUO) model in rats in vivo. UUO animal model is a classic model to investigate renal fibrosis (Yu et al, 2020). In the present study, we ligated the left ureter of rats to establish UUO rats and chose 80 mg/kg NE-THCQ for animal study based on the preexperiment (Supplementary Figure 2).…”

In Vitro and In Vivo Antifibrotic Effects of Fraxetin on Renal Interstitial Fibrosis via the ERK Signaling Pathway

“…In gentamicin-induced nephrotoxicity, renal corpuscles and tubules pre-treated with resveratrol exhibit restored glutathione and catalase activity, decreased malondialdehyde content, increased E-cadherin expression, and decreased expression of α-SMA, TGF-β, and collagen [ 10 ]. The kidneys of UUO mice treated with ruxolitinib were observed to have lower levels of collagen deposition, α-SMA activation, TGF-β expression, inflammatory responses, malondialdehyde, and cleaved caspase-3 as well as elevated total superoxide dismutase arising from attenuation of ERK and Stat3 phosphorylation [ 11 ].Taken together, in this study we found that fraxetin had anti-fibrotic effects by decreasing the expression of α-SMA, collagen, N-cadherin and vimentin through down-regulation of the ERK signaling pathway. Although some evidences demonstrated that EMT may play an important role in renal fibrosis, EMT is still one of several mechanisms for renal fibrosis.…”

“…During the EMT, kidney tubule cells lose their epithelial characteristics and adopt a mesenchymal phenotype [ 8 , 9 ]. Studies show that blocking the trans-differentiation of renal tubule cells prevents EMT-induced inflammation, oxidative stress, and apoptosis by mediating transforming growth factor β (TGF-β) pathways [ 10 , 11 , 12 ]. Oxidative stress, inflammation, and the EMT are also caused by the uremic toxin indoxyl sulfate, a tryptophan metabolite that accumulates during CKD progression.…”