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FOXO4 enhances high glucose-induced HK-2 cell damage and inflammation by targeting TFPI2 in diabetic nephropathy
1Department of General Medicine, First Hospital of Hebei Medical University, Shijiazhuang, China.
Background:
Diabetic nephropathy (DN) represents the leading cause of end-stage renal disease; however, its molecular mechanisms remain incompletely understood. This study aims to elucidate the specific roles and regulatory mechanisms of Tissue factor pathway inhibitor 2 (TFPI2) and forkhead box O4 (FOXO4) in DN.
Methods:
Differentially expressed genes were identified from the GSE30529 dataset. TFPI2 expression in renal tubules was predicted using the kidney interactive transcriptomics database. Gene expression was examined using reverse transcription-polymerase chain reaction and western blot assay. Functional outcomes were examined using cell counting kit 8, 5‑ethynyl2'‑deoxyuridine, flow cytometry, TUNEL assays, and corresponding commercial assay kits. The relationship between TFPI2 and FOXO4 was analyzed by GeneCards and JASPAR websites, and dual luciferase reporter and chromatin immunoprecipitation assays. DN model mice were constructed to analyze the role of TFPI2 in vivo.
Results:
TFPI2 was significantly increased in DN patients and high glucose (HG)-stimulated HK-2 cells. TFPI2 down-regulation mitigated HG-induced HK-2 cell damage, inflammation, and oxidative stress. Mechanistically, FOXO4 targeted and promoted the transcription of TFPI2. FOXO4 down-regulation alleviated HG-induced HK-2 cell injury by targeting TFPI2. In vivo, TFPI2 knockdown inhibited damage and inflammation.
Conclusion:
FOXO4 promotes HG-induced HK-2 cell damage and inflammation via regulating TFPI2 in vitro. Furthermore, TFPI2 knockdown alone alleviates renal injury and inflammation in vivo.
Insights
Forkhead box O4 (FOXO4) promotes diabetic nephropathy (DN) by increasing Tissue factor pathway inhibitor 2 (TFPI2) in kidney cells. Reducing TFPI2 lessens kidney damage and inflammation in DN.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Diabetic nephropathy (DN) is a major cause of end-stage renal disease.
- The precise molecular mechanisms underlying DN pathogenesis are not fully understood.
- Investigating novel molecular players like TFPI2 and FOXO4 is crucial for understanding DN.
Purpose of the Study:
- To elucidate the roles of Tissue factor pathway inhibitor 2 (TFPI2) and forkhead box O4 (FOXO4) in diabetic nephropathy (DN).
- To understand the regulatory mechanisms between TFPI2 and FOXO4 in the context of DN.
- To evaluate the therapeutic potential of targeting TFPI2 in DN.
Main Methods:
- Differential gene expression analysis using the GSE30529 dataset.
- In vitro studies using high glucose-stimulated HK-2 cells to assess cell damage, inflammation, and oxidative stress.
- In vivo studies using a mouse model of DN to evaluate the effects of TFPI2 knockdown.
Main Results:
- TFPI2 expression was significantly elevated in DN patients and high glucose-treated cells.
- Downregulation of TFPI2 reduced high glucose-induced cell damage, inflammation, and oxidative stress.
- FOXO4 was identified as a transcriptional regulator of TFPI2, and its downregulation also alleviated cellular injury.
Conclusions:
- FOXO4 promotes high glucose-induced kidney cell damage and inflammation by regulating TFPI2.
- TFPI2 knockdown demonstrated a protective effect against renal injury and inflammation in vivo.
- Targeting the FOXO4-TFPI2 axis may offer a therapeutic strategy for diabetic nephropathy.
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