Altered expression of Tau protein and its role in renal injury during chronic kidney disease = 만성콩팥병에서 Tau 단백질의 발현 변화와 신손상 기전

다국어 초록 (Multilingual Abstract)

Chronic kidney disease (CKD) is a progressive and irreversible disorder characterized by nephron loss, tubular atrophy, and interstitial fibrosis, ultimately leading to end-stage kidney disease. Although significant advances have been made in understanding CKD pathogenesis, the molecular mechanisms that mediate renal structural injury remain incompletely defined. Tau, a microtubule-associated protein known for its critical role in maintaining cytoskeletal stability in neurons, has been extensively studied in the context of neurodegenerative diseases. However, its potential function in the kidney and contribution to CKD have not been elucidated. In this study, we sought to determine whether tau protein is involved in CKD pathophysiology and to explore its mechanistic and therapeutic implications. Tau expression was examined in both human CKD kidney tissues and in three murine models of CKD: unilateral ureteral obstruction (UUO), folic acid–induced CKD (FA-CKD), and adenine diet–induced CKD (AD-CKD). Renal function, histopathological features, and molecular alterations were assessed in parallel. Furthermore, disease severity was investigated in tau transgenic mice (P301S model), and a tau-targeting antibody was administered to evaluate potential therapeutic effects. In human CKD kidneys, total tau and phosphorylated tau levels were significantly elevated compared with controls. In murine CKD models, total tau, phosphorylated tau, and acetylated tau (ac-Tau) were all markedly increased. Increased tau expression was associated with reduced renal function and greater degrees of tubular dilatation and interstitial fibrosis. Immunohistochemical and immunofluorescent analyses showed that tau was predominantly localized in proximal tubular epithelial cells, with additional signals detected in glomerular compartments such as podocytes and mesangial cells. In P301S tau transgenic mice, CKD induction resulted in more severe renal injury and functional decline compared with non-transgenic littermates. Conversely, administration of a tau-specific antibody significantly reduced tubular injury, collagen deposition, and tau accumulation in AD-CKD mice, supporting the therapeutic potential of tau inhibition. Mechanistically, tau dysregulation appeared to contribute to cytoskeletal remodeling in the kidney. Acetylated tau was strongly localized along the luminal surface of tubular epithelial cells, suggesting a structural association with microtubule organization within injured tubules. These findings indicate that tau alterations may influence cellular architecture during CKD progression. This study provides the first evidence that tau is actively involved in renal pathology. Tau accumulation and post-translational modifications, such as phosphorylation and acetylation, may amplify oxidative and inflammatory signaling, contributing to tubular degeneration and fibrosis. These results establish tau as a novel pathological mediator linking cytoskeletal instability and CKD progression. Targeting tau may therefore represent a promising therapeutic approach to mitigate renal injury and fibrosis, particularly in aging populations where both CKD and tau-related disorders are prevalent.

목차 (Table of Contents)

• List of tables ⅳ
• List of Figures ⅴ
• Abstract ⅶ
• Ⅰ. Introduction 1
• 1. Pathophysiological mechanisms of chronic kidney disease 1
• 2. Biological characteristics and pathological roles of Tau protein 2
• 3. Potential link between CKD and Tau protein dysfunction 3
• 4. Study rationale and objectives 4
• Ⅱ. Materials and Methods 6
• 1. Human samples 6
• 2. Animal models of CKD 8
• 3. Blood and urine analysis 8
• 4. Histopathology 9
• 5. Immunohistochemistry and immunofluorescence 9
• 6. Quantitative RT-PCR 9
• 7. Western blot 10
• 8. Statistical analysis 10
• 9. Experimental overview 10
• Ⅲ. Results 14
• 1. Tau protein expression is increased in human chronic kidney disease 14
• 2. Tau accumulates in multiple murine CKD models 20
• 3. Tau expression correlates with disease severity in AD-CKD 27
• 4. P301S Tau transgenic mice show aggravates CKD phenotypes 35
• 5. Tau antibody administration ameliorates tubular injury in CKD 42
• Ⅳ. Discussion 45
• 1. Tau protein as a novel pathological mediator in chronic kidney disease 45
• 2. Systemic expression of Tau and its relevance beyond the central nervous system 46
• 3. Post-translational modifications of Tau and pathogenic signaling pathways in CKD 47
• 4. Cellular implications, therapeutic perspectives, and study limitations 48
• Ⅴ. Conclusion and future perspectives 50
• References 51
• 국문 초록 55
• 감사의 글 58