Tau, microtubule-associated protein, is upregulated and promotes kidney damage in chronic kidney disease

Abstract

Background: Tau, a microtubule-associated protein, has a well-established role in neurodegenerative disorders, but its function in the kidney and contribution to chronic kidney disease (CKD) remain unclear. Although emerging data suggest the role of tau in CKD pathogenesis, the mechanisms of tau-mediated renal injury are not well defined. In this context, we investigated tau expression in CKD and its potential link to disease progression.

Methods: Tau protein levels were measured in kidneys from CKD patients and three murine CKD models: unilateral ureteral obstruction (UUO), folic acid-induced CKD (FA-CKD), and adenine diet-induced CKD (AD-CKD). Renal functional and histological parameters were assessed. Disease progression was further evaluated in P301S tau transgenic mice. To assess potential therapeutic effects, a tau-specific antibody was administered to the AD-CKD mouse model.

Results: Expression of tau-including total, phosphorylated, and acetylated forms-was markedly elevated in the kidneys of CKD patients and across all three CKD mouse models (UUO, FA-CKD, and AD-CKD). This elevation correlated with worsening renal function, tubular injury, and kidney fibrosis. Tau was upregulated as CKD progressed, and was predominantly observed in proximal tubular epithelial cells, but was also detected in glomerular podocytes and mesangial cells. In tau transgenic mice, tau accumulation worsened renal dysfunction and pathological changes, while administering a tau-specific antibody in AD-CKD mice reduced renal tau levels and improved both tubular dilatation and fibrosis.

Conclusion: Tau is upregulated during CKD progression and contributes to tubular injury and fibrosis. Targeting tau could offer a new therapeutic approach for reducing renal injury in CKD.