Norcantharidin Inhibits Renal Interstitial Fibrosis by Blocking the Tubular Epithelial-Mesenchymal Transition

Abstract

Epithelial–mesenchymal transition (EMT) is thought to contribute to the progression of renal tubulointerstitial fibrosis. Norcantharidin (NCTD) is a promising agent for inhibiting renal interstitial fibrosis. However, the molecular mechanisms of NCTD are unclear. In this study, a unilateral ureteral obstruction (UUO) rat model was established and treated with intraperitoneal NCTD (0.1 mg/kg/day). The UUO rats treated with NCTD showed a reduction in obstruction-induced upregulation of α-SMA and downregulation of E-cadherin in the rat kidney (P<0.05). Human renal proximal tubule cell lines (HK-2) stimulated with TGF-β1 were treated with different concentrations of NCTD. HK-2 cells stimulated by TGF-β1 in vitro led to downregulation of E-cadherin and increased de novo expression of α-SMA; co-treatment with NCTD attenuated all of these changes (P<0.05). NCTD reduced TGF-β1-induced expression and phosphorylation of Smad2/3 and downregulated the expression of Snail1 (P<0.05). These results suggest that NCTD antagonizes tubular EMT by inhibiting the Smad pathway. NCTD may play a critical role in preserving the normal epithelial phenotype and modulating tubular EMT.

RNA‐Seq analysis of potential lncRNAs and genes for the anti‐renal fibrotic effect of norcantharidin

“…[6][7][8] In the kidney, our studies have shown that NCTD could profoundly prevent tubular EMT, inhibit the extracellular matrix (ECM) synthesis and accumulation in kidney, attenuate proteinuria and interstitial inflammation, and prevent the progression of many kinds of renal disease. [9][10][11][12] Furthermore, our clinical studies also confirmed that NCTD could reduce the proteinuria of chronic glomerular nephritis, but showed no apparently hepatorenal toxicity and bone marrow suppression (data unpublished). Mechanistically, the anti-fibrotic effect of NCTD was associated with its antagonistic effects on tubular EMT and ECM synthesis by suppressing activation of TGF-β1/Smad2/3 signaling, repressing NF-κB expression and dephosphorylation of β-catenin mediated by PP2A (data unpublished).…”

Induced Pluripotent Stem Cells Inhibit Bleomycin-Induced Pulmonary Fibrosis in Mice through Suppressing TGF-β1/Smad-Mediated Epithelial to Mesenchymal Transition

“…Moreover, TGF-β1 plays a predominant role in EMT process and has been recognized as a primary inducer of EMT during pulmonary fibrosis (Chen et al, 2014). Previous studies demonstrated that TGF-β1 could enhance the expression level of zinc-finger transcriptional factor Snail, which subsequently suppressed the transcription of E-cadherin (Thiery et al, 2009; Li et al, 2013). Hence, we speculated that the inhibitory effect of iPS cells on EMT in BLM-induced mice might be associated with the suppression of TGF-β1-Smad signaling activation.…”

Advanced Oxidation Protein Products Induce Hypertrophy and Epithelial-To-Mesenchymal Transition in Human Proximal Tubular Cells through Induction of Endoplasmic Reticulum Stress

“…CKD is known to progress to end-stage renal disease through the final common pathway of renal interstitial fibrosis [1]. Although the cellular mechanisms that facilitate tubulointerstitial fibrosis and the contribution of tubular epithelial-to-mesenchymal transition (EMT) to renal interstitial fibrosis are still controversial, tubular EMT is through to play a role in the pathogenesis of CKD [2,3,4,5,6,7,8].…”