Abstract
The dysfunction of salivary glands commonly induces dry mouth, infections, and dental caries caused by a lack of saliva. This study was performed to determine the genetic and functional changes in salivary glands using a klotho (-/-) mouse model. Here, we confirmed the attenuation of KLF4 expression in the salivary glands of klotho (-/-) mice. Soluble klotho overexpression induced KLF4 transcription and KLF4-mediated signaling pathways, including mTOR, AMPK, and SOD1/2. Silencing klotho via siRNA significantly down-regulated KLF4 expression. Additionally, we monitored the function of salivary glands and soluble klotho and/or KLF4 responses and demonstrated that soluble klotho increased the expression of KLF4 and markers of salivary gland function (α-amylase, ZO-1, and Aqua5) in primary cultured salivary gland cells from wild type and klotho (-/-) mice. In a 3D culture system, cell sphere aggregates were observed in soluble klotho- or KLF4-expressing cells and exhibited higher expression levels of salivary gland function-related proteins than those in nontransfected cells. These results suggest that activation of the klotho-mediated KLF4 signaling pathway contributes to potentiating the function of salivary glands.
Highlights
Salivary gland dysfunctional changes occur with reduced salivary flow and dry mouth and commonly involve oral dysfunction, tooth structure deterioration, and infection through reduced salivation [1, 2]
To elucidate the relationship between klotho and Kruppel-like factor 4 (KLF4) gene expression, we evaluated KLF4 mRNA expression using real-time quantitative RT-PCR in wild-type and klotho (-/-) mouse embryonic fibroblasts (MEFs)
Soluble klotho facilitates various cellular functions, including antiaging effects, and has tissue protective effects that are independent of fibroblast growth factor 23 (FGF23)/FGFR
Summary
Salivary gland dysfunctional changes occur with reduced salivary flow and dry mouth (xerostomia) and commonly involve oral dysfunction, tooth structure deterioration, and infection through reduced salivation [1, 2]. Aging induces atrophy of acinar cells (ACs) and replacement of normal gland parenchyma with adipose tissue, connective tissue, and oncocytes [3, 4]. Numerous medical drugs and treatments (radiation, chemotherapy) have been shown to significantly contribute to salivary gland dysfunction [5, 6]. Changes associated with salivary gland dysfunction are affected by multiple factors, such as the environment, not all changes are considered to be physiologic, and how aging influences the function of salivary glands is unclear. Klotho is a transmembrane protein and a putative antiaging agent. Klotho-knockout mice demonstrate agerelated phenotypes, such as a short lifespan, growth retardation, infertility, skin atrophy, hypoglycemia, hyposalivation, hyperphosphatemia, ectopic calcification, osteoporosis and pulmonary emphysema [7, 8]
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