Journal of advanced research · 2025
Podocyte TLR4 deletion alleviates diabetic kidney disease through prohibiting PKCδ/SHP-1-dependent ER stress and relieving podocyte damage and inflammation.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Li Zongze, Tan Di, Lin Jiangong, Zhang Tingwei, Liu Bing, Zhao Bing, Liang Decai, Li Li, Wei Xufeng, Lv Zhimei, Wang Rong, Hu Mengsi
Аннотация
INTRODUCTION: Toll-like receptor 4 (TLR4) has emerged as a crucial factor in the pathogenesis of various kidney disease including diabetic kidney disease (DKD), whereas its intricate role in the complex pathophysiology of DKD and associated diabetic podocyte injury remains inadequately elucidated.
OBJECTIVES: In this study we aimed to investigate the regulatory role and mechanism of TLR4 dysregulation in diabetic podocyte injury.
RESULTS: Upregulation of TLR4 was demonstrated in high glucose (HG)-challenged podocytes and in streptozocin (STZ)-induced diabetic renal tissue. Mechanistically, TLR4 signaling activation upon hyperglycemia stimulation, mediated by its adaptor protein myeloid differentiation factor 88 (MyD88), initiated a downstream protein kinase C delta (PKCδ)/Src homology-2 domain-containing phosphatase-1 (SHP-1) signaling cascade. This cascade subsequently triggered endoplasmic reticulum (ER) stress and release of the inflammatory chemokine monocyte chemotactic protein 1 (MCP-1), which exacerbated damage to slit diaphragm (SD) proteins and disrupted cytoskeletal structure, enhanced cell motility, and promoted inflammation in podocytes. Podocyte-specific deletion of TLR4 was able to alleviate diabetic podocyte injury and proteinuria by interrupting these abnormalities, and thereby to reinstate the integrity of the SD, rectify the effacement of foot processes (FPs), and reduce proteinuria, confirming a pivotal role of the TLR4/MyD88/PKCδ/SHP-1 axis in vivo.
CONCLUSIONS: These findings elucidated the involvement of the TLR4/MyD88/PKCδ/SHP-1 signaling cascade in diabetic podocyte injury and inflammation, provided evidence for the renal protective and therapeutic potential of podocyte-specific targeting TLR4 in the challenge of DKD and might shed light on therapeutic strategies in proteinuric diseases.
OBJECTIVES: In this study we aimed to investigate the regulatory role and mechanism of TLR4 dysregulation in diabetic podocyte injury.
RESULTS: Upregulation of TLR4 was demonstrated in high glucose (HG)-challenged podocytes and in streptozocin (STZ)-induced diabetic renal tissue. Mechanistically, TLR4 signaling activation upon hyperglycemia stimulation, mediated by its adaptor protein myeloid differentiation factor 88 (MyD88), initiated a downstream protein kinase C delta (PKCδ)/Src homology-2 domain-containing phosphatase-1 (SHP-1) signaling cascade. This cascade subsequently triggered endoplasmic reticulum (ER) stress and release of the inflammatory chemokine monocyte chemotactic protein 1 (MCP-1), which exacerbated damage to slit diaphragm (SD) proteins and disrupted cytoskeletal structure, enhanced cell motility, and promoted inflammation in podocytes. Podocyte-specific deletion of TLR4 was able to alleviate diabetic podocyte injury and proteinuria by interrupting these abnormalities, and thereby to reinstate the integrity of the SD, rectify the effacement of foot processes (FPs), and reduce proteinuria, confirming a pivotal role of the TLR4/MyD88/PKCδ/SHP-1 axis in vivo.
CONCLUSIONS: These findings elucidated the involvement of the TLR4/MyD88/PKCδ/SHP-1 signaling cascade in diabetic podocyte injury and inflammation, provided evidence for the renal protective and therapeutic potential of podocyte-specific targeting TLR4 in the challenge of DKD and might shed light on therapeutic strategies in proteinuric diseases.