Yuanyuan Wang1, Yanwen Mao1, Xiaohuan Zhang1, Huiming Liu1, Wei Peng1, Luqun Liang1, Mingjun Shi1, Ying Xiao1, Yingying Zhang1, Fan Zhang1, Rui Yan2, Bing Guo3. 1. State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou 550025, China; Department of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China. 2. Department of Nephrology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, China. Electronic address: yanrui@gmc.edu.cn. 3. State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou 550025, China; Department of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou 550025, China; Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China. Electronic address: guobingbs@126.com.
Abstract
AIMS: This study aimed to investigate the role of transforming growth factor-β-activated protein kinase 1(TAK1) in the development of diabetic nephropathy (DN) by regulating the protein stability of Ski-related novel protein N(SnoN). MAIN METHODS: A combination of in vivo and in vitro model systems was used to investigate how TAK1 regulated the expression of SnoN protein in DN. The study determined the effects of modulating the expression or activity of TAK1 on the SnoN protein level and its influence on the epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition. KEY FINDINGS: Under the high-glucose condition, the activation of TGF-β1/TAK1-induced phosphorylation and ubiquitination of SnoN protein resulted in reduced SnoN protein level as a consequence of enhanced SnoN degradation, which promoted EMT and ECM deposition in renal tubular epithelial cells. The study showed that TAK1 impaired SnoN protein level by decreasing the protein stability of SnoN. SIGNIFICANCE: TAK1 mediated the phosphorylation of SnoN, resulting in SnoN ubiquitination and eventual degradation, which enhanced EMT and ECM deposition to promote renal fibrosis during DN.
AIMS: This study aimed to investigate the role of transforming growth factor-β-activated protein kinase 1(TAK1) in the development of diabetic nephropathy (DN) by regulating the protein stability of Ski-related novel protein N(SnoN). MAIN METHODS: A combination of in vivo and in vitro model systems was used to investigate how TAK1 regulated the expression of SnoN protein in DN. The study determined the effects of modulating the expression or activity of TAK1 on the SnoN protein level and its influence on the epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition. KEY FINDINGS: Under the high-glucose condition, the activation of TGF-β1/TAK1-induced phosphorylation and ubiquitination of SnoN protein resulted in reduced SnoN protein level as a consequence of enhanced SnoN degradation, which promoted EMT and ECM deposition in renal tubular epithelial cells. The study showed that TAK1 impaired SnoN protein level by decreasing the protein stability of SnoN. SIGNIFICANCE: TAK1 mediated the phosphorylation of SnoN, resulting in SnoN ubiquitination and eventual degradation, which enhanced EMT and ECM deposition to promote renal fibrosis during DN.