Aberrant tau regulation Promotes Tubular Injury and Fibrosis in Chronic Kidney Disease

Tau, a microtubule-associated protein, is well known for its role in neurodegenerative disorders, where its post-translational modification and aggregation lead to neuronal dysfunction. Although tau has been found in peripheral organs, including the kidney, its physiological role outside the nervous system is not yet well understood. This study is the first to investigate tau expression in chronic kidney disease (CKD), demonstrating its upregulation in renal tissues and potential contribution to tubular injury and fibrosis.

MAPT gene and protein expression in kidney tissues from CKD patients and mice were examined by immunohistochemistry (IHC) and single-cell RNA sequencing. In murine models, tau expression was assessed in three types of CKD models: unilateral ureteral obstruction (UUO; control and UUO, n = 4 each), folic acid–induced (FA-CKD; control and FA-CKD, n = 4 each), and adenine diet–induced CKD (AD-CKD) at 1, 2, and 4 weeks (n = 4 per time point). Renal function was assessed by measuring BUN, creatinine, cystatin C, and uACR, and histological analyses were performed using PAS, Masson's trichrome, and Sirius Red staining. Total tau (t-Tau), phosphorylated tau (p-Tau Ser396), and acetylated tau (ac-Tau) were analyzed by Western blotting, IHC, and immunofluorescence. P301S hTau transgenic mice (WT control, WT AD-CKD, P301S control, P301S AD-CKD; each with n = 3–6 per group) were subjected to the same AD-CKD protocol and compared with wild-type AD-CKD mice. Finally, for therapeutic evaluation, an ac-Tau–specific antibody (50 mg/kg IP) was administered to four groups (control, AD-CKD, AD-CKD + control IgG, and AD-CKD + ac-Tau antibody; each with n = 10 per group).

IHC and single-cell RNA sequencing revealed a significant increase in renal tau expression in both CKD patients and mouse models compared to controls, predominantly localized in the proximal tubules. In all three murine CKD models (UUO, FA-CKD, and AD-CKD), t-Tau, p-Tau, and ac-Tau levels were significantly elevated relative to controls, accompanied by more severe tubular injury and interstitial fibrosis. In the AD-CKD model, tau expression was higher in CKD mice than in controls and progressively increased with disease duration (1, 2, and 4 weeks). The degree of tau expression strongly correlated with tubular dilatation (r = 0.8) and fibrotic area (r = 0.7) (both p < 0.001). P301S mice exhibited aggravated CKD phenotypes, showing increased BUN, cystatin C, α-SMA, and 8-OHdG levels compared with wild-type AD-CKD mice (p < 0.01). Conversely, in AD-CKD mice with elevated tau expression, tubular dilatation, and upregulated fibrotic markers (α-SMA, COL1A1), treatment with an ac-Tau-specific antibody markedly attenuated these pathological changes, restored AQP1-positive tubules, and reduced oxidative stress (8-OHdG) (all p < 0.01). Notably, tau expression levels closely paralleled the severity of interstitial fibrosis and oxidative stress, suggesting a causal relationship between tau upregulation and renal parenchymal remodeling during CKD progression.

Increased tau expression represents a prominent pathological feature in both human and experimental CKD, predominantly affecting proximal tubular epithelial cells. Tau upregulation exacerbates renal injury and fibrosis, whereas its inhibition ameliorates pathological changes. Targeting aberrant tau expression may offer a promising therapeutic strategy for CKD.