Triiodothyronine enhances various forms of kidney-specific Klotho protein and suppresses the Wnt/β-catenin pathway: Insights from in-vitro, in-vivo and in-silico investigations

Saswat Kumar Mohanty; Amaresh Kumar Mohanty; Muthuvel Suresh Kumar; Kitlangki Suchiang

doi:10.1016/j.cellsig.2024.111214

Triiodothyronine enhances various forms of kidney-specific Klotho protein and suppresses the Wnt/β-catenin pathway: Insights from in-vitro, in-vivo and in-silico investigations

Cell Signal. 2024 May 9:120:111214. doi: 10.1016/j.cellsig.2024.111214. Online ahead of print.

Authors

Saswat Kumar Mohanty¹, Amaresh Kumar Mohanty², Muthuvel Suresh Kumar², Kitlangki Suchiang³

Affiliations

¹ Department of Biochemistry and Molecular Biology, Pondicherry University, Pondicherry 605 014, India. Electronic address: mohantysk7.5@pondiuni.ac.in.
² Department of Bioinformatics, Pondicherry University, Pondicherry 605014, India.
³ Department of Biochemistry, North Eastern Hill University, Shillong, Meghalaya 793022, India. Electronic address: kitlangkisuchiang@nehu.ac.in.

PMID: 38729322
DOI: 10.1016/j.cellsig.2024.111214

Abstract

Age-related diseases are intricately linked to the molecular processes underlying aging, with the decline of the antiaging protein Klotho being a key factor. Investigating these processes is crucial for developing therapeutic strategies. The age-associated reduction in Klotho expression, coupled with a decline in the endocrine hormone triiodothyronine (T3), prompted a detailed exploration of their potential interplay. Our research, conducted through both in-vitro and in-vivo studies on BALB/c mice, unveiled a significant capacity of T3 to upregulate various forms of Klotho via ATF-3/p-c-Jun transcription factor. This effect was particularly noteworthy in aged individuals, where Klotho expression had waned compared to their younger counterparts. Importantly, T3 demonstrated a promising therapeutic impact in rejuvenating Klotho expression in this context. Further investigations elucidated the molecular mechanisms underlying T3's impact on aging-related pathways. In-vitro and in-vivo experiments established T3's ability to downregulate the Wnt/β-Catenin pathway by enhancing Klotho expression. In-silico analyses provided insights into Klotho's intricate role, showing its capacity to inhibit Wnt ligands such as Wnt3 and Wnt8a, consequently disrupting their interaction with the Wnt receptor. Additionally, T3 was found to downregulate kidney-specific GSK-3β expression through the augmentation of Klotho expression. The study also highlighted T3's role in maintaining calcium and phosphate homeostasis via Klotho. This comprehensive investigation not only sheds light on the intricate mechanisms governing aging processes but also presents promising avenues for therapeutic interventions targeting the Wnt/β-Catenin pathway implicated in various age-associated diseases.

Keywords: Aging; GSK-3β; Klotho; Triiodothyronine; Wnt/ β-catenin pathway.