Diabetic cardiomyopathy (DCM) is a major complication of type 2 diabetes mellitus (T2DM) that leads to significant morbidity and mortality. The alteration in the signaling mechanism in diabetes leading to cardiomyopathy remains unclear. The purpose of this study is to investigate the role of tauopathy in myocardial dysfunction observed in T2DM. In that regard, diabetic Sprague Dawley rats were treated with intraperitoneal injections of lithium chloride (LiCl), inhibiting tau phosphorylation. Cardiac function was evaluated, and molecular markers of myocardial fibrosis and the TGF-β signaling were analyzed. T2DM rats exhibited a decline in ejection fraction and fractional shortening that revealed cardiac function abnormalities and increased myocardial fibrosis. These changes were associated with tau hyperphosphorylation. Treating diabetic rats with LiCl attenuated cardiac fibrosis and improved myocardial function. Inhibition of GSK-3β leads to the suppression of tau phosphorylation, which is associated with a decrease in TGF-β expression and regulation of the pro-inflammatory markers, suggesting that tau hyperphosphorylation is parallelly associated with fibrosis and inflammation in the diabetic heart. Our findings provide evidence of a possible role of tau hyperphosphorylation in the pathogenesis of DCM through the activation of TGF-β and by inducing inflammation. Targeting the inhibition of tau phosphorylation may offer novel therapeutic approaches to reduce DCM burden in T2DM patients.

Background: Diabetic kidney disease (DKD) represents a chronic microvascular complication with diabetes, affecting around one-third of diabetic individuals. Despite current therapies, progression to end-stage kidney disease remains a challenge. Abnormal hyperphosphorylation of the Tau protein is implicated in various age-related diseases. This study aimed to explore the link between renal Tau protein hyperphosphorylation and kidney damage in type 2 diabetes mellitus (T2DM). Methods: Sprague Dawley rats were administered lithium chloride (LiCl), an inhibitor of a glycogen synthase kinase-3 (GSK3) inhibitor known to reduce Tau hyperphosphorylation. LiCl was administered either daily or every other day at a dosage of 1 mmol/kg. The effects of LiCl on kidney function were assessed through proteinuria, the kidney-to-bodyweight ratio, inflammation, fibrosis, and TGF-β1 expression levels. Results: Diabetic rats exhibited increased proteinuria, renal hypertrophy, inflammation, fibrosis, and elevated TGF-β1 expression. Lithium chloride treatment reduced kidney hypertrophy, inflammation, and fibrosis, indicating that Tau hyperphosphorylation contributes to the pathogenesis of DKD. LiCl also regulated TGF-β1 expression, which was associated with improved renal outcomes. Conclusions: The inhibition of Tau hyperphosphorylation by lithium chloride offers a potential therapeutic strategy for mitigating kidney damage in diabetic kidney disease. This study proposes LiCl as a novel treatment approach to attenuate DKD progression.