TEAD1 Regulates Fibroblast Activation and Renal Fibrosis in CKD

Background: A key pathological feature of chronic kidney disease (CKD) is renal interstitial fibrosis, which is characterized by extensive fibroblast activation and accumulation of extracellular matrix (ECM). 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 fibroblast activation and kidney fibrosis during the development of CKD. Methods: Lentivirus transfection was utilized to knock down the expression of TEAD1 in fibroblast cells in vitro. Cultured fibroblast cells were treated with TGF-β1 to examine the role of TEAD1 in regulating fibroblast activation. PDGFRβ-specific TEAD1 knockout (TEAD1PKO) mice were generated by crossing TEAD1 floxed mice (TEAD1CON) with tamoxifen-inducible PDGFRβ-driven cre recombinase mice. Ten-week-old male TEAD1PKO mice and TEAD1CON mice were subjected to unilateral ureteral obstruction (UUO) or intraperitoneally injected with folic acid (250 mg/kg) to induce renal fibrosis. Blood and kidneys were collected for analysis of kidney function, fibroblast activation, collagen deposition, ECM production and kidney fibrosis. Results: In cultured fibroblast cells, knockdown of TEAD1 using shRNA enhanced TGF-β1-induced expression levels of fibronectin and α-SMA while overexpression of TEAD1 suppressed TGF-β1 induced fibroblast activation and ECM production. Moreover, dual-luciferase assay revealed that knockdown of TEAD1 potentiated TGF-β1 induced α-SMA promoter activity. Proteomic analysis identified Runt-related transcription factor2 (RUNX2) as a potential TEAD1 interacting protein which was confirmed by co-IP analysis. In vivo, TEAD1 expression was highly upregulated following UUO and folic acid injury. TEAD1PKO mice exhibited exacerbated kidney dysfunction as reflected by higher BUN levels compared with TEAD1CON mice following folic acid nephropathy. In response to UUO or folic acid nephropathy, TEAD1PKO mice had increased ECM accumulation and enhanced collagen deposition compared with TEAD1CON mice. Conclusion: Taken together, our results identify TEAD1 as an important regulator in fibroblast activation and kidney fibrosis. Therefore, targeting TEAD1 could represent a novel therapeutic approach for attenuating CKD progression. Funding: NIDDK Support