Kidney research and clinical practice · 2026
FOXO4 enhances high glucose-induced HK-2 cell damage and inflammation by targeting TFPI2 in diabetic nephropathy.
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Mu Liqin, Zhao Yu, Li Yang, Gao Wei, Wang Jing
Аннотация
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.
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.