Mechanism Study on How PTX3 Drives EMT and Fibrosis of RenalTubular Epithelial Cells in Diabetic Kidney Disease by Activating theJNK Pathway

Background: Diabetic kidney disease (DKD) is characterized by tubular EMT and fibrosis. So far, the pathogenesis of DKD is still not fully understood. Pentraxin 3 (PTX3), an inflammatory regulator, is overexpressed in DKD due to hyperglycemia. PTX3 amplifies inflammation by promoting inflammatory cytokine release (TNF-α, IL-6) and activating the nuclear factor kappa-B (NF-κB) pathway. Subsequently, it triggers the c-Jun N-terminal kinase (JNK) signaling pathway, enhancing AP-1-mediated transcription of inflammatory genes (MCP-1, ICAM-1). JNK also upregulates EMT markers (α-SMA, N-cadherin) through increased transforming growth factor TGF-β1, accelerating renal fibrosis. Targeting the PTX3-JNK axis with neutralizing antibodies or inhibitors mitigates inflammation and EMT, suggesting PTX3 as a potential anti-fibrotic target in DKD. Objective: We believe that PTX3 induces EMT in HK-2 cells to further lead to fibrosis by activating the JNK signaling pathway. Thus, investigate the role of Pentraxin 3 (PTX3) in diabetic kidney disease (DKD) and explore the therapeutic potential of targeting the PTX3-JNK signaling pathway. Methods: Human renal tubular epithelial cells (HK-2) were stimulated with high glucose (HG); a DKD mouse model was established using streptozotocin (STZ) induction; and renal biopsy tissues were collected from DKD patients. PTX3 expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunofluorescence. Recombinant human PTX3 protein (Rh-PTX3) was added to HK-2 cells to examine the expression of EMT markers (E-cadherin, α-SMA, Vimentin, N-cadherin, Snail) and the key JNK pathway molecule (p- JNK). The JNK inhibitor SP600125 was used to assess changes in EMT and fibrosis. In vitro experiments were conducted using human renal tubular epithelial cells (HK-2) stimulated with high glucose (HG) in (The Key Laboratory of Nephrology) facilities. A DKD mouse model was established through streptozotocin (STZ) induction in (C57). Renal biopsy tissues were obtained from DKD patients at (The Second Hospital of Lanzhou University) between (2024-09-01) and (2025-09-01). PTX3 expression was detected by qRT-PCR. Western blotting and immunofluorescence. Recombinant human PTX3 protein (Rh-PTX3) was added to HK-2 cells to examine the expression of EMT markers (E-cadherin, α-SMA, Vimentin, N-cadherin, Snail) and the key JNK pathway molecule (p-JNK). The JNK inhibitor SP600125 was used to assess changes in EMT and fibrosis. Data collection occurred between (2024-09-01) and (2025-09-01). Results: PTX3 expression was significantly increased in the HG cell model and DKD models, accompanied by EMT and JNK pathway activation. The JNK inhibitor reversed the EMT phenotype induced by PTX3 overexpression. Discussion: This study reveals that PTX3 promotes renal fibrosis in DKD by activating the JNK pathway, leading to EMT of renal tubular epithelial cells. This finding, supported by clinical samples, animal models, and cell experiments, suggests PTX3-JNK signaling as a potential therapeutic target for DKD. Conclusion: PTX3 promotes renal tubular EMT and fibrosis by activating the JNK signaling pathway. Targeting the PTX3-JNK axis may provide a novel therapeutic strategy for DKD.