Interactions between Tau Phosphorylation and Endoplasmic Reticulum Stress in Diabetic Nephropathy

Tau is a microtubule-associated protein whose abnormal phosphorylation disrupts the cytoskeleton and induces cell death. While its role is well known in neuro degenerative diseases, its function in kidney pathology, particularly diabetic nephropathy (DN), is not well understood.

DN was induced in NADPH oxidase 5 (NOX5) pod+ mice through a high-fat diet (HFD; 60% kcal fat) for 3, 6, and 12 weeks. Kidney tissues and cultured mesangial cells were analyzed for tau phosphorylation at specific residues (Ser202 and Thr205), fibrosis markers (e.g., α-smooth muscle actin), and endoplasmic reticulum (ER) stress. Tau phosphorylation was modulated using thousand and one amino acid kinase inhibitor and ER stress inhibitors. Immunohistochemistry was also performed on human renal biopsy samples from DN patients.

pTau Ser202 and Thr205 expression levels were elevated by 6 weeks of the HFD and remained persistently upregulated at 12 weeks. Human biopsy analysis further revealed elevated pTau Ser202 and Thr205 expression in the patients with DN, which correlated with proteinuria. In NOX5 pod+ mice, early metabolic changes developed by HFD led to tau phosphorylation and kidney damage. Transforming growth factor β-induced fibrosis or thapsigargin-induced ER stress increased tau phosphorylation, while inhibiting tau phosphorylation or ER stress alleviated mesangial cell damage.

Our findings demonstrate that site-specific tau phosphorylation is associated with renal injury in DN and may serve as a potential marker of disease severity. The interplay between tau phosphorylation and ER stress appears to contribute to disease progression. Targeting tau phosphorylation and its upstream stress pathways may offer new therapeutic strategies for DN.