A Dual intervention of Triiodothyronine and Baicalein bi-directionally upregulates Klotho with attenuation of chronic kidney disease and its complications in aged BALB/c mice

Abstract

Chronic kidney disease (CKD) presents a pressing global health challenge, characterized by progressive renal function decline and heightened morbidity and mortality. The interplay between CKD and hypothyroidism, particularly through the non-thyroidal low triiodothyronine (T3) syndrome, exacerbates disease progression and elevates mortality rates. Perturbations in the hypothalamic-pituitary-thyroidal (HPT) axis contribute to this scenario, while fibrotic kidneys exhibit diminished levels of the protective protein Klotho due to abnormal activation of the Wnt/β-catenin pathway. Leveraging our previous findings showcasing T3's ability to downregulate aberrant Wnt/β-catenin pathway activity by enhancing Klotho expression, both in vitro and in vivo, and Baicalein's direct inhibition of the Wnt pathway in C. elegans, we investigated Klotho's potential as a molecular link between CKD and hypothyroidism. Through experiments utilizing an adenine-induced CKD aged mouse model, we aimed to enhance Klotho expression via exogenous T3 administration and bidirectional Wnt pathway blockade using Baicalein (BAI). Our results demonstrate a significant synergistic upregulation of Klotho expression with combined T3 and BAI treatment, surpassing the effects of individual treatments. Moreover, this combination therapy effectively suppressed aberrant signaling molecules such as transforming growth factor beta (TGF), nuclear factor kappa B (NFκB), and glycogen synthase kinase 3 (GSK3), thus mitigating renal fibrosis. Improvements were observed in CKD-induced complications including cardiovascular disorders, dyslipidemia, and alterations in bone and serum markers. This unique bidirectional approach, targeting Klotho biology directly enhanced by T3 and sustained by T3 coupled with Wnt pathway blockade using BAI, presents a promising strategy for CKD management. Particularly relevant for elderly CKD patients with hypothyroidism, this approach holds potential to ameliorate renal degradation. Our findings underscore the substantial therapeutic promise of hormone and natural chemical interventions in CKD management.