NDRG2 knockdown promotes fibrosis in renal tubular epithelial cells through TGF-β1/Smad3 pathway.

Abstract

Renal fibrosis is a common pathological pathway of various chronic kidney diseases progressing to end-stage renal disease and is characterized by tubular atrophy, fibroblast/myofibroblast activation and excessive deposition of extracellular matrix (ECM). N-Myc downstream-regulated gene-2 (NDRG2) is reported to be associated with liver fibrosis in rats. However, the biological function of NDRG2 in renal fibrosis remains unclear. Therefore, we investigate the effect of NDRG2 on renal fibrosis and the underlying mechanism of NDRG2 in TGF-β1-induced renal tubular epithelial cells (HK-2). Our results show that TGF-β1 down-regulates NDRG2 mRNA and protein expression in HK-2 cells. Moreover, NDRG2 knockdown dramatically reduces the TGF-β1-induced protein and mRNA of E-cadherin and increases the TGF-β1-induced protein and mRNA expression level of α-SMA, Vimentin, Snail, Col-I, Col-III and FN; this is reversed by NDRG2 overexpression. Furthermore, NDRG2 silencing significantly increases the phosphorylation level of Smad3 (p-Smad3), which is decreased by NDRG2 overexpression, although these have no effect on the protein expression of p-Smad2 and Smad7. In addition, SIS3, a specific inhibitor of Smad3 phosphorylation, partly reverses the effect of NDRG2 knockdown on the protein and mRNA expression of epithelial-mesenchymal transition (EMT) markers and ECM components in TGF-β1-induced HK-2 cells. Taken together, our results indicate that NDRG2 knockdown promotes renal fibrosis through its effect on the protein and mRNA expression of EMT markers and ECM components by regulating the downstream Smad3 signaling pathway in renal tubular epithelial cells. Modulation of NDRG2 expression might provide a new therapy for renal fibrosis.

• Authors: Zhibo Jin, Chaohui Gu, Fengyan Tian, Zhankui Jia, Jinjian Yang
• Journal: Cell and tissue research (Cell Tissue Res) Vol. 369 Issue 3 Pg. 603-610 (09 2017) ISSN: 1432-0878 [Electronic] Germany
• PMID: 28646304 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NDRG2 protein, human
• RNA, Messenger
• Smad3 Protein
• Transforming Growth Factor beta1
• Tumor Suppressor Proteins

Topics

• Cell Line
• Down-Regulation (drug effects)
• Epithelial Cells (metabolism)
• Epithelial-Mesenchymal Transition (genetics)
• Extracellular Matrix (drug effects, metabolism)
• Fibrosis
• Gene Knockdown Techniques
• Humans
• Kidney Tubules (pathology)
• RNA, Messenger (genetics, metabolism)
• Signal Transduction
• Smad3 Protein (metabolism)
• Transforming Growth Factor beta1 (metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)