TEAD1 Regulates Tubular Epithelial-Cell Dedifferentiation and Kidney Fibrosis

Background: A prominent pathological feature of chronic kidney disease (CKD) is renal fibrosis, which is characterized by excessive accumulation of extracellular matrix (ECM). In fibrosis, tubular epithelial cells (TECs) undergo dedifferentiation leading to reduced expression of characteristic epithelial markers and increased expression of mesenchymal markers. Despite recent advances in our understanding of the mechanisms of renal fibrosis, the molecular mechanisms remain poorly understood. In this study, we examined the role of TEA domain family member 1 (TEAD1) in regulating TEC dedifferentiation during the development of CKD. Methods: Cultured TECs were used to examine the role of TEAD1 in regulating TEC dedifferentiation, G2/M cycle arrest, and cellular senescence. Proximal tubule-specific TEAD1 knockout (TEAD1PKO) mice were generated by crossing TEAD1 floxed mice with PEPCK-Cre mice. Ten-week-old male TEAD1PKO mice and TEAD1f/f (TEAD1CON) mice were intraperitoneally injected with folic acid (250 mg/kg) or vehicle (0.3mM NaHCO3) to induce renal fibrosis. Blood and kidneys were collected at 14 days for analysis of kidney function, TEC dedifferentiation, inflammation, fibroblast activation, collagen deposition and fibrosis. Results: In cultured TECs, knockdown of TEAD1 using shRNA promoted TEC dedifferentiation and ECM protein production. Additionally, knockdown of TEAD1 markedly induced p-H3 and p21 levels indicating G2/M cycle arrest which was associated with increased senescence-associated β-galactosidase activity. In contrast, overexpression of TEAD1 prevented tubular cell dedifferentiation and ECM protein production, and markedly reduced p-H3 and p21 expression. In vivo, TEAD1 expression was significantly induced in kidneys of mice with folic acid injury. Following folic acid injury, TEAD1PKO mice exhibited kidney dysfunction as reflected by higher BUN levels compared with TEAD1CON mice. Moreover, TEAD1PKO mice had increased inflammatory cytokines, enhanced fibroblast activation and upregulated total collagen deposition and ECM proteins, which was associated with p-H3 and p21 induction compared with TEAD1CON mice. Conclusion: Taken together, our results indicate that TEAD1 plays an important role in regulating TEC dedifferentiation and fibrosis. Therefore, targeting TEAD1 could represent a novel therapeutic approach for attenuating CKD progression. Funding: NIDDK Support, Veterans Affairs Support