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

Yi-Hsien Hsieh,Yong-Syuan Chen,Tung-Wei Hung,Yi-Ning Huang,Chu-Che Lee,Jen-Pi Tsai,Hui-Ling Chiou

doi:10.3390/toxins13070474

Abstract

Fraxetin, a natural derivative of coumarin, is known to have anti-inflammatory, anti-oxidant, and hepatoprotective effects in multiple diseases and in liver fibrosis. Whether fraxetin exerts similar effects against renal fibrosis is unknown. In a Unilateral Ureteral Obstruction (UUO) mouse model of renal fibrosis, fraxetin decreased UUO-induced renal dysfunction with a marked reduction in renal interstitial collagen fibers as detected by Masson’s Trichrome staining. Fraxetin treatment also inhibited the expression of α-SMA, Collagen I, Collagen IV, fibronectin, N-cadherin, vimentin, phosphorylated-ERK, and increased the expression of E-cadherin in UUO mice, as shown by immunohistochemical staining and western blot analysis. In vitro studies showed that fraxetin and indoxyl sulfate had no cytotoxic effects on MES13 kidney cells, but that fraxetin significantly decreased IS-induced cell motility and decreased protein expression of α-SMA, N-cadherin, vimentin, and Collagen IV via the ERK-mediated signaling pathway. These findings provide insight into the mechanism underlying fraxetin-induced inhibition of fibrogenesis in renal tissue and suggest that fraxetin treatment may be beneficial for slowing CKD progression.

Highlights

We observed that fraxetin significantly decreased the collagen IV, collagen I, and fibronectin protein expressions in the kidneys of Ureteral Obstruction (UUO) mice compared to the UUO mice (Figure 1B)
Fraxetin markedly reduced the accumulation and expression of α-SMA protein in the kidneys of UUO mice (Figure 1C,D). These results suggest that fraxetin improves renal function and reduces the damage and pro-fibrotic effects in UUO mouse kidneys
The kidneys of UUO mice treated with ruxolitinib were observed to have lower levels of collagen deposition, α-SMA activation, transforming growth factor β (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

Summary

Introduction

Chronic kidney disease (CKD) is one of the most common chronic health conditions in developed countries. The multiplicity of risk factors for CKD contributes to its high prevalence. CKD is a major health issue, with high co-morbidities and mortality. Many CKD patients are unaware of their condition until the disease has progressed to an advanced stage [1,2]. Regardless of the etiology of CKD, renal fibrosis represents the final pathway leading to end-stage renal disease [3]. As CKD progresses, uremic toxins accumulate and contribute to overall organ dysfunction [4]. Treatment strategies include medications to treat the primary disease, avoidance of nephrotoxic agents, and

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Conclusion