Klotho-Dependent Role of 1,25(OH)2D3 in the Brain
Miribane Dërmaku-Sopjania Fatbardhë Kurtib Nguyen Thi Xuanc Mentor Sopjanib
aDepartment of Chemistry, University of Prishtina, Prishtinë, Kosova, bFaculty of Medicine, University of Prishtina, Prishtinë, Kosova, cInstitute of Genome Research, Vietnam Academy of Science and Technology, Cau Giay, Hanoi, Vietnam
Key Words
Brain • 1,25(OH)2D3 • Klotho • Fibroblast growth factor
Abstract
The antiaging protein Klotho is encoded by the Klotho gene first identified as an 'aging suppressor', in mice. Klotho deficiency is involved in premature aging and early death, while its overexpression is related to longevity. Klotho is mostly expressed in the kidney, but also in the brain, and in other organs. Two forms of Klotho, the cell membrane and secreted form, have pleiotropic activities that include regulation of general metabolism, oxidative stress, and mineral metabolism that correlates with its effect on accelerating aging. Membrane Klotho serves as an obligate co-receptor for the fibroblast growth factor (FGF), while secreted Klotho plays its role as a humoral factor. Klotho protein participates in the regulation of several biological activities, including regulation of calcium-phosphate homeostasis and PTH as well as vitamin D metabolism. The active form of vitamin D, 1,25(OH)2D3 (1,25-dihydroxy-vitamin D3 = calcitriol), acts as a neurosteroid that participates in the regulation of multiple brain functions. It provides neuroprotection and suppresses oxidative stress, inhibits inflammation and inflammatory mediators, and stimulates various neurotrophins. Calcitriol is involved in many brain-related diseases, including multiple sclerosis, Alzheimer´s disease, Parkinson´s disease, and schizophrenia. This review covers the most recent advances in Klotho research and discusses Klotho-dependent roles of calcitriol in neuro-psycho-pathophysiology.
Introduction
Aging is a complex and multifactorial process characterized by age-related changes. This biological phenomenon is driven by the delicate interaction between multiple genetic and environmental factors [1, 2]. The intrinsic complexity of aging still remains a challenge to be fully elucidated. However, it is well known that age-related processes are influenced by the alteration of particular gene expression and involve numerous intracellular signaling pathways. A complex interplay between age-related genes and various signaling pathways needs to be better understood. It is well known that aging is characterized by an increased incidence of various human diseases, including diabetes [3], hypertension [4], neurological disorders [5], chronic kidney disease (CKD) [6], and increased risk of cardiovascular diseases [7]. One of the genes involved in aging is the Klotho gene, an aging suppressor gene. Therefore, potential medications targeting the Klotho expression may slow down the process of aging and postpone the onset of age-dependent diseases. The therapeutic intervention of Klotho may have significant clinical relevance.
Klotho gene encodes a single-pass transmembrane protein with multiple anti-aging effects [8]. The Klotho family of proteins has three members with pleiotropic functions: αKlotho (known as Klotho) encoded by the main αKlotho gene, and two other Klotho proteins βKlotho and γKlotho, encoded by two other Klotho-related genes, β-Klotho and γ-Klotho [9]. The αKlotho gene is primarily expressed in the kidney, more in the distal convoluted tubule (DCT) cells, and less in the renal proximal convoluted tubule (PCT) cells [8-11]. Klotho is synthesized in large amounts in the brain by the brain choroid plexus epithelial cells [12, 13], hippocampal neurons, and Purkinje EC cells. To a lesser extent, Klotho is also present in the cerebral white matter [14]. Low expression of αKlotho has been reported in other body parts, including the pituitary gland, thyroid gland, urinary bladder, placenta, skeletal muscle, aorta, ovary, colon, pancreas, and testis [8, 15, 16].
Similar to other signaling molecules such as AMP-activated protein kinase [17-22] and Janus kinase 2 [23-27], Klotho is involved in various processes, including regulation of cellular transport systems and cell volume regulation [9, 11, 28-31]. Noteworthy, the Klotho gene was first identified in mice, as an 'aging suppressor'. A Klotho gene-deficient mouse has phenotypes resembling human premature aging [9], while gene overexpression in mice is characterized by an increased lifespan [32]. The mouse klotho (mKL) gene and the human αKlotho gene (hKL) are very similar [33].
Two protein molecules are produced by the Klotho gene, the membrane-bound, and the secreted form. Secreted Klotho protein, known as soluble or circulating Klotho, arises either by proteolytic cleavage of the extracellular domain of the full length αKlotho just above the cell surface [8, 34] or by alternative splicing of mRNA Klotho gene that generates a secreted Klotho isoform 70 kDa [35] (Fig. 1). Although both forms of Klotho protein have their distinct biological activities, most of the Klotho functions are attributed to secreted Klotho [9, 36] that may function in different roles, including its role as a humoral factor [30, 37] through an unknown plasma membrane receptor [38], and as an enzyme regulating the various plasma membrane glycoproteins [39, 40], and through it influencing several signaling pathways [41, 42]. The main function of membrane Klotho protein is to serve as an obligatory co-receptor for fibroblast growth factor 23 (FGF23) through forming a complex with FGF receptors on the cell membrane, which participates in various biological processes, including the regulation of Pi and 1,25(OH)2D3 metabolism, which is a critical hallmark in the development of chronic diseases. As many recent studies revealed, the biological effects of Klotho proteins appear to be much broader. The underlying molecular mechanisms of Klotho effects are not fully understood. However, Klotho is involved in different intracellular signaling pathways, as reviewed elsewhere [9, 33], such as regulating FGF23-mediated signaling, cAMP, p53/p21, PKC, insulin/insulin-like growth factor-1 (insulin/IGF-1), and Wnt signaling pathways. Klotho is involved in various different physiological and pathological processes. There are still poor data about the direct role of Klotho in the human central nervous system, brain diseases respectively. In older human community-dwelling adults, lower plasma Klotho has been reported to be associated with a significant increase in all-cause mortality, including cognitive impairment, but the biological mechanisms remain unclear [43]. However, Klotho is critical for the maturation of oligodendrocytes, myelin integrity, and prevent myelin degeneration [44]. The neural Klotho protein can protect hippocampal neurons against amyloid formation, glutamate toxicity [44], and against the development of neurodegenerative diseases related to aging as confirmed in mice [45]. Calcitriol is an important regulator of mineral metabolism [46]. Due to its ability to induce Klotho, calcitriol has anti-aging/wellness functions. Therefore, normal levels of calcitriol are associated with anti-aging effects [47-49]. The plasma levels of calcitriol and Klotho are decreased with age.
The role of Klotho in calcitriol synthesis
FGF23, a protein, is a member of the FGF19 subfamily, composed of 251-amino acids in length (approx. 32 kDa), synthesized and secreted by bone cells, predominantly osteoblast [50, 51]. FGF23 has an N-terminal fragment binding domain for the FGF receptor (FGFR) and a C-terminal binding domain for Klotho [52, 53]. Klotho is involved in the FGF23-signaling. Specifically, FGF23 requires a binary complex of membrane αKlotho protein as an obligate co-receptor and FGFR for activation of FGFR/αKlotho binary receptor complexes located on the cell membrane [54]. These FGF23/α-Klotho co-mediated activities have been implicated in several functions. Therefore, the cell membrane expression of both FGFR and Klotho proteins defines the target tissues for FGF23. Synthesis and secretion of FGF23 from the bone are stimulated by the parathyroid hormone (PTH), vitamin D (1,25(OH)(2)D), and by dietary and serum phosphate levels [55]. In the bone FGF23 synthesis is inhibited the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and by dentin matrix protein 1 (DMP1) [56] (Fig. 2).
The Klotho/FGFR complex is obligatory for eliciting the FGF23-induced intracellular signaling events [57]. This pathway participates in several diseases [58-60] and controlling numerous biological functions, including 1,25(OH)2D3 synthesis and its breakdown. FGF23 overexpression inhibits biosynthesis of 1,25(OH)2D3 and the renal phosphate reabsorption [60, 61], whereas FGF23 deficiency results in much higher levels of serum 1,25(OH)2D3, thus causing hyperphosphatemia, accompanied by soft-tissue calcification [1, 54, 55]. FGF23 overexpression mediated hypophosphatemia is caused by down-regulating the expression of renal sodium-coupled phosphate cotransporter, NaPi2a, and NaPi2c [62], resulting in elevated phosphate excretion through the urine. The antiaging protein Klotho has a key role in calcium homeostasis, an effect that is realized either through 1,25(OH)2D3 inhibition or by other pathways [63, 64].
The FGF23/Klotho pathway regulates 1,25(OH)2D3 levels by modulating the expression levels of enzymes involved in the synthesis and degradation of 1,25(OH)2D3, in the kidney (Fig. 1). Specifically, FGF23/Klotho downregulates the 25-hydroxyvitamin D 1-α-hydroxylase (Cyp27b1) that catalyze the synthesis of the active form of vitamin D (1,25(OH)2D3) and upregulates the 1,25-dihydroxyvitamin D 24-hydroxylase (Cyp24a1) that catalyzes the breakdown of the 1,25(OH)2D3 into inactive calcitroic acid [65]. FGF23/Klotho pathway functions as a counter-regulatory phosphaturic hormone for vitamin D.
Multiple roles of 1,25(OH)2D3 in the brain
The active form of vitamin D and vitamin D receptors (VDR: vitamin D receptor; PDIA3: Protein-Disulphide-Isomerase, family A member 3) are reported to be expressed throughout the brain tissues [66], particularly in regions that are central to learning and memory. This has led to the paradigm that preventing calcitriol deficiency or insufficiency may have a key role in preserving cognitive function, indicating that 1,25(OH)2D3 may prevent, or even treat, age-related cognitive diseases [49, 67].
The 1,25(OH)2D3 is considered a neurosteroid that participates in multiple brain functions. However, the cerebral expression of 1,25(OH)2D3-associated enzymes and receptors remains unclear [68]. Like other nuclear steroids, within the brain, 1,25(OH)2D3 may trigger both genomic and major auto-/paracrine non-genomic actions. An overview of the roles of the 1,25(OH)2D3 in the brain is presented in Fig. 3.
The role of 1,25(OH)2D3 in brain development and function
Over the last decade, numerous studies reported an important role of 1,25(OH)2D3 in brain development and function [49, 69]. Studies suggest 1,25(OH)2D3 plays a neuroprotective role through withstanding greater oxidative stress, as reported in experiments using primary cortical neuronal cultures and of different biomarkers of oxidative stress [69]. Additionally, 1,25(OH)2D3 is reported to be a vital factor for the growth, survival, and proliferation of the neurons [69], neurotransmission, brain development, and immunomodulation [68, 70], with a potential to treat various neurodegenerative diseases.
1,25(OH)2D3 in the neuropsychiatric and other diseases
Optimal levels of 1,25(OH)2D3 are important for normal functions of the brain, but either deficient and excessive levels of vitamin D may lead to brain dysfunctioning [49]. The antiaging properties of 1,25(OH)2D3 are primarily attributed to its ability to induce Klotho. The decreased levels of 1,25(OH)2D3 are followed by a decrease in phosphate and calcium plasma concentrations [39, 57], while deficient levels of phosphate and calcium induce 1,25(OH)2D3 formation. The hypocalcemia-induced parathyroid hormone leads to 1,25(OH)2D3 formation as well. Conversely, phosphate excess stimulates FGF23, which in turn inhibits 1,25(OH)2D3 formation. FGF23 requires Klotho to become effective [9, 33, 71]. This vitamin has powerful effects in the brain unnecessary related to mineral metabolism. 1,25(OH)2D3 is involved in many processes in the brain function [49] as well as in neuropsychiatric diseases [49, 67, 72, 73] (Fig. 3) such as Multiple sclerosis (MS) [74], a progressive disease of the central nervous system (CNS), which is characterized by damage to the myelin sheath surrounding axons of nerve cells. The immunomodulatory effects of 1,25(OH)2D3 have been widely reported during the last years. The results of the last study using the animal model of CNS inflammation reported that calcitriol downregulates both, blood-brain barrier disruption and local macrophage/microglia Activation, and prevents neuroinflammation [74]. 1,25(OH)2D3 may potentially serve as a therapy for treating MS patients. 1,25(OH)2D3 deficiency is closely associated with depressive symptoms, especially in older adults. Another neurodegenerative disease where 1,25(OH)2D3 is involved is Parkinson's disease (PD). The progressive neurodegeneration in PD is characterized by neuroinflammation and endothelial vascular impairment. The vitamin D receptor (VDR) is expressed in the brain including the dopamine neurons and brain endothelial cells; however, its role in the regulation of endothelial biology has not been clearly characterized in terms of PD. A recent study reported that brain endothelial P-glycoprotein (P-gp, encoded by MDR1a gene) level is down-regulated in PD through the VDR-mediated pathway [75]. This result indicates that a dysfunctional VDR-P-gp pathway may be used as a possible target for the maintenance of vascular homeostasis during pathological conditions in PD. 1,25(OH)2D3 has also been used for neuroprotective treatment for COVID-19 [72], a disease caused by infection with a novel coronavirusSARS-CoV-2 [71]. Recent clinical trials suggest the importance of using 1,25(OH)2D3 supplementation to reduce the incidence of acute respiratory infection and the severity of the respiratory tract in COVID-19 adults and children.
The most common cause of dementia is Alzheimer's disease (AD), a progressive disorder that degenerates brain cells. One of the major pathological features of AD is the accumulation of Amyloid-beta (Aβ). The 1,25(OH)2D3 through its nuclear hormone receptor, VDR, may be exploited for the treatment of Aβ pathology [73]. The mechanisms of action of 1,25(OH)2D3 are at least partly understood. Specifically, 1,25(OH)2D3 exerts its role via an interplay with glial cell line-derived neurotrophic factor (GDNF)-signaling as well as through restoring the downregulation of GDNF and inhibiting the phosphorylation of the phosphatidylinositol 3 kinase (PI3K)/protein kinase B/Akt/glycogen synthase kinase-3β (GSK-3β) signaling pathway. There is an association between 1,25(OH)2D3 deficiency and psychiatric disorders. A similar correlation has been suggested regarding 1,25(OH)2D3 and bipolar disorder (BD). However, in most of the studies, no significant differences in the levels of 1,25(OH)2D3 between BD patients and other psychiatric disorders were confirmed [67]. This does not rule out that an appropriate 1,25(OH)2D3 status may have a positive role in mood balance due to its immunomodulatory, antidepressant, and other functions.
1,25(OH)2D3 plays a role in brain metastatic cancer and acute myeloid leukemia (AML) [76]. A combination of 1,25(OH)2D3 and the hypomethylating agent (HMA) 5-Azacytidine (AZA) Increases cytotoxicity and differentiation, as well as decreases the proliferation of primary AML patient samples and several AML cell lines used in that study.
An ischemic stroke leads to blood-brain barrier (BBB) dysfunction, which is a physical and biochemical barrier that precisely maintains cerebral homeostasis. 1,25(OH)2D3 has been reported to protect against cerebral ischemia by maintaining BBB permeability, increasing the level of brain-derived neurotrophic factor (BDNF) in their brains, and decreasing PPARγ-mediated neuroinflammation [77]. 1,25(OH)2D3-induced regulation of GDNF/Ret signaling is also involved in dopaminergic neurons [78]. Hence, indicating its important role in dopamine physiology. Ret, a receptor for GDNF-family ligands, is directly regulated by 1,25(OH)2D3 through VDR in dopaminergic neurons. 1,25(OH)2D3-mediated effect via VDR is implied in the expression of various dopaminergic-associated genes [70], and, thus, in dopamine neuronal development and maturation.
Conclusion
The antiaging protein Klotho is implied in numerous processes, including the development of multiple-age-related diseases when deficient. Klotho has been reported to be involved in various biological functions and in the regulation of many intracellular signaling pathways [9, 33], including cAMP, p53/p21, PKC, and Wnt. Klotho is an obligatory cofactor for the activation of FGF23-dependent intracellular signaling. Klotho, in an FGF23-dependent and FGF23-independent manner, participates in the regulation of 1,25(OH)2D3 formation and phosphate and calcium metabolism [9, 11, 47, 79]. Klotho increases the resistance to oxidative stress and protects cells and tissues from oxidative damage [80, 81]. Klotho participates in the regulation of 1,25(OH)2D3. This vitamin is implied in numerous brain functions, under physiological and pathophysiological conditions [49, 69, 70, 72, 73, 76, 78]. Due to its reported role in cognitive impairments and neurodegenerative diseases, the therapeutic use of 1,25(OH)2D3 or related agonists in the treatment of several neuropsychiatric disorders and other conditions may represent great potential. 1,25(OH)2D3 mediated brain actions could be genomic and non-genomic [49, 69]. However, the interaction of genomic and non-genomic processes of 1,25(OH)2D3 is largely unexplored. The detailed molecular mechanisms by which 1,25(OH)2D3 exerts its actions in the brain remains incompletely understood, especially regarding cell-specific variations and the stage of development in the brain. This needs further study efforts to better understand the precise mechanisms associated with specific functional outcomes.
Acknowledgments
MS drafted the initial manuscript and coordinated finalizing. MDS helped in drafting and contributed to finalizing the manuscript. FK and XNT contributed to finalizing the manuscript.
Funding
This work was supported by the Italmed, Kosova.
Statement of Ethics
The authors have no ethical conflicts to disclose.
The authors have no conflicts of interest to declare.
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