FOXA1 Suppresses SATB1 Transcription and Inactivates the Wnt/β-Catenin Pathway to Alleviate Diabetic Nephropathy in a Mouse Model

Abstract

Objective Diabetic nephropathy (DN) represents the most common diabetic complication that may lead to end-stage renal disease. This work focused on the effect of FOXA1 on the DN development and the molecular mechanism. Methods A mouse model of DN was induced by high-fat diets and streptozotocin. The concentrations of blood glucose and urinary protein in mice, and the pathological changes in mouse kidney tissues were determined. A podocyte cell line MPC-5 was treated with high glucose (HG) to mimic a DN-like condition in vitro. FOXA1 and SATB1 were overexpressed in HG-treated MPC-5 cells and in DN mice to explore their effects on cell proliferation and apoptosis, and on pathological changes in mouse kidney tissues. The binding relationship between FOXA1 and STAB1 was predicted and validated. Activation of the Wnt/β-catenin pathway was detected. Results FOXA1 was poorly expressed in the kidney tissues of DN mice. Overexpression of FOXA1 reduced the concentrations of fasting blood glucose and 24-h urinary protein in mice. It also suppressed the accumulation of glomerular mesangial matrix and hyperplasia of glomerular basement membrane, and reduced collagen deposition and interstitial fibrosis in mouse kidney. Also, FOXA1 reduced HG-induced apoptosis of MPC-5 cells. FOXA1 bound to the promoter region of SATB1 for transcription suppression. Overexpression of SATB1 activated the Wnt/β-catenin pathway and blocked the protective roles of FOXA1 in DN mice and in HG-treated MPC-5 cells. Conclusion This study demonstrated that FOXA1 transcriptionally suppresses SATB1 expression and inactivates the Wnt/β-catenin signaling pathway, thereby inhibiting podocyte apoptosis and DN progression.

Bioinformatics analysis identifies diagnostic biomarkers and their correlation with immune infiltration in diabetic nephropathy

“…Moreover, preventing MAPK activation, which inhibits inflammation and apoptosis, can ameliorate renal fibrosis (52). Furthermore, inactivation of the WNT/β-catenin signaling pathway can inhibit podocyte apoptosis and DN progression (53). Overall, these findings are consistent with our data mining results.…”

E3 ubiquitin ligase neural precursor cell‐expressed developmentally downregulated gene 4 motivates FOXA1 ubiquitination and restrains proliferation of diffuse large B‐cell lymphoma cells via the Wnt/β‐Catenin pathway

“…FOXA1 has been reported to restrain SATB1 transcription and inactivate the Wnt/β‐Catenin pathway to mitigate diabetic nephropathy in a mouse model (Zhu et al, 2021). The Wnt/β‐Catenin pathway has been clarified to be elevated in cancer and takes a major role in proliferation, invasion, apoptosis, and angiogenesis (Vallée et al, 2021).…”

“…To further explore the link between FOXA1 and NEDD4, it was elevated FOXA1 in FARAGE cells with enhancive NEDD4 and detected an elevation in FOXA1 (Figure 5a). Subsequent FOXA1 has been reported to restrain SATB1 transcription and inactivate the Wnt/β-Catenin pathway to mitigate diabetic nephropathy in a mouse model (Zhu et al, 2021). The Wnt/β-Catenin pathway has been clarified to be elevated in cancer and takes a major role in proliferation, invasion, apoptosis, and angiogenesis (Vallée et al, 2021).…”

The Role of FOXA1 in Human Normal Development and Its Functions in Sex Hormone-Related Cancers

“…On the other hand, Vatamaniuk et al [96] demonstrated that Foxa1-deficient mice exhibited impaired insulin secretion due to uncoupled oxidative phosphorylation. Zhu et al [97] showed that FOXA1 suppressed the transcription of special AT-rich sequence binding protein 1 and inactivated the Wnt/β-catenin pathway to alleviate diabetic nephropathy in a mouse model. However, the role of FOXA1 in the relationship between diabetes and breast cancer remains to be determined in future studies.…”