Pharmacological Efficacy and Mechanism of Vitamin D in the Treatment of "Kidney-Brain" Disorders

*Jia-Li Zhang, Yong-Jun Wang and Yan Zhang*

## **Abstract**

Accumulating evidences have shown that serum 25-hydroxyvitamin D concentrations were inversely correlated with the incidence or severity of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and that vitamin D deficiency might be associated with an increased susceptibility to many of the complications accompanied by COVID-19, such as disorders in kidney and brain. Our previous experimental studies demonstrated that vitamin D and its analogs could protect from kidney diseases, neuroinflammation, and musculoskeletal disorders such as osteoporosis and muscle atrophy, through the suppressive effects on overactivation of the renin-angiotensin system (RAS) in tissues. Moreover, we published a review describing the therapeutic effects of traditional Chinese medicine (TCM) for organ injuries associated with COVID-19 by interfering with RAS. In the TCM principle "Kidney dredges brain," this chapter will emphasize the potential preventive and therapeutic effects of vitamin D on both renal injuries and central nervous system disorders in COVID-19 patients and further elucidate the pharmacological effects with underlying mechanisms of vitamin D in "Kidney-Brain" disorders.

**Keywords:** vitamin D receptor, kidney, brain, renin-angiotensin system, traditional Chinese medicine, vitamin D

## **1. Introduction**

The outbreak of Coronavirus Disease 2019 (COVID-19) has created a global public health crisis. Observational studies provided evidence that serum 25-hydroxyvitamin D [25(OH)D] concentration was inversely correlated with the incidence or severity of COVID-19 [1]. Moreover, very severe vitamin D deficiency (<10 ng/ml) was considerably more common in COVID-19 patients than in non-COVID-19 ones [2]. Consistently, a significant correlation between vitamin D sufficiency and reduction in clinical severity and inpatient mortality from COVID-19 disease has been explored [3, 4].

Actually, as vitamin D is concerned, traditional Chinese medicine (TCM) and Western medicine could share similar philosophical logic to fight against COVID-19, mainly because in TCM theory, the pathogenesis of COVID-19 is closely associated with cold dampness, which could be attenuated by sun exposure and Wen-Yang herbs, both of which could restore the blood level of vitamin D in Western medicine [5]. Clinically, TCM medications have been exhibiting benefits in decreasing the rate of disease progression, time to the resolution of fever, and rate of progression to severe COVID-19 cases [6], and we published a review summarizing the pharmacological interventions and the underlying mechanisms of TCM for organ injuries associated with COVID-19 [7].

As we know, the renal 1α-OHase enzyme catalyzes the biosynthesis of active vitamin D, 1,25(OH)2D3, and conversely, the 24-OHase enzyme in the kidney deactivates vitamin D via hydroxylation at site 24 on the chemical structure of 25(OH)D and 1,25(OH)2D3. In our group, we have published a series of research articles uncovering that the kidney-tonifying herb Fructus Ligustri Lucidi could manage vitamin D metabolism and enhance circulating 1,25(OH)2D3 level [8–10]. Intriguingly, there are TCM theories supporting the relevance between kidney and brain, such as "Interaction between Kidney and Brain," and "Kidney dominates bone, and dredges brain," *etc.*, where the biological basis for this interaction might be attributed to vitamin D. Therefore, the effects and the mechanisms of vitamin D on comorbidity in kidney and brain of COVID-19 patients are elaborated in this chapter.

## **2. Vitamin D and kidney injuries**

## **2.1 Clinical practice**

Several previous studies have demonstrated that the risk of COVID-19 and associated death increases with the coexistence of various underlying diseases, including liver and kidney failure, cerebrovascular disease, chronic obstructive pulmonary disease, coronary heart disease, hypertension, diabetes, and so forth [11–16]. Among those comorbid diseases, the incidence of kidney injuries in the general population after infection with SARS-CoV-2 was around 3–15%, 14.5–50% in patients with severe COVID-19 infection in the intensive care unit, and even higher in patients with chronic kidney disease (CKD), which is related to severe infection and higher fatality rate in COVID-19 patients [17, 18]. In a retrospective case-control study from a Los Angeles Health System, Chang *et al.* [19] observed that renal diseases were the predominant premorbid risk factors for COVID-19 patients. In New York, a longitudinal prediction study at two centers showed that the death rate in COVID-19 patients accompanied by acute kidney injury (AKI) is approximately five times that of mortality in non-AKI patients (31.5% and 6.9%) and that the COVID-19 patients developed AKI about 3 days after hospitalization [20].

A growing body of evidence suggests that vitamin D and COVID-19 are linked. The first study to examine whether the last vitamin D status before COVID-19 testing is associated with COVID-19 test results of 489 patients was published after the outbreak of the COVID-19 pandemic. This single-center retrospective cohort study concluded that adults with hypovitaminosis D were more likely to be infected by SARS-CoV-2 [21]. Similarly, in 20 European countries, substantial inverse associations between mean blood 25(OH)D concentrations and the frequency of COVID-19 cases and mortality were discovered [22]. The above data illustrate the close

## *Pharmacological Efficacy and Mechanism of Vitamin D in the Treatment of "Kidney-Brain"… DOI: http://dx.doi.org/10.5772/intechopen.105820*

correlation between serum vitamin D levels and the risk rate of developing COVID-19. In addition, at the same time, studies found that vitamin D supplementation could reduce the risk of being infected with SARS-CoV-2. As presented in a retrospective cohort study done in Switzerland, vitamin D supplementation reduced the probability of SARS-CoV-2 infections [23]. Furthermore, frequent vitamin D3 supplementation, at least in the elderly, in boluses taken routinely throughout the year preceding diagnosis, has indicated a reduction in the risk of mortality and clinical improvement in old COVID-19 patients [24]. In a short term, randomized, placebo-controlled trial in 25(OH)D deficient (<20 ng/mL) COVID-19 individuals from India, 62.5% of those treated with 60,000 IU/1500 μg/day of vitamin D3 for 7–14 days were negative for SARS-CoV-2 after 21 days, compared with just 20.8% of those who were not given vitamin D3 [25].

Vitamin D is a vital protector for inhibiting inflammation and cytokine storms in the kidney [26]. The correlations were demonstrated between low vitamin D levels and the risk of influenza infection. Same as influenza, different studies showed that vitamin D status could influence the outcome of COVID-19 patients, including kidney injuries [27]. In Spain, a retrospective cohort clinical trial was held to compare whether the administration or not of oral calcifediol could alleviate mortality risk and the underlying diseases arising from COVID-19 [24]. Among the 537 included COVID-19 patients, those who received calcifediol (0.266 mg/capsule, two capsules on entry, and then one capsule on days 3, 7, 14, 21, and 28) were more likely to have a low rate of CKD and even mortality [24]. The COVID-19 patients accompanied by CKD with maintenance hemodialysis have a very high 3-month mortality rate, but researchers found that the same type of patient treated with active vitamin D had a lower risk of mortality caused by COVID-19 [28]. The facts all indicated that either serum vitamin D status or vitamin D supplementation has a strong link with the degree of severity of kidney injuries associated with COVID-19.

## **2.2 Mechanism studies**

## *2.2.1 Renin-angiotensin system (RAS)*

SARS-CoV-2 enters cells when its spike proteins are bound to angiotensin-converting enzyme 2 (ACE2) receptors, which are the potent negative regulators on the RAS and are highly expressed in the kidney [7]. The excess activity of the renal RAS, characterized as the increased production of angiotensin II (Ang II), is responsible for kidney destruction, inflammation, and functional failure related to SARS-CoV-2 [29].

Vitamin D inhibits renin expression and in turn reduces Ang II expression, thus, serving as a negative RAS regulator [29, 30]. The deficiency of vitamin D activates the intrarenal RAS, thereby inducing an increase in the level of Ang II, which is an important stimulator of kidney injury [31, 32]. Our study demonstrated that active vitamin D analogs paricalcitol and doxercalciferol were able to suppress RAS activation, alleviate glomerular and tubulointerstitial damage, and reduce proteinuria in streptozotocin (STZ, 40 mg/kg)-induced diabetic DBA/2 J mice [33, 34]. Similarly, treatment of STZ (60 mg/ kg)-induced type 1 diabetic rats with calcitriol (0.2 μg/kg, i.g.) significantly reduced urine albumin and improved glomerular ultrastructure by reducing the renin expression and alleviating the oxidative stress of the kidneys [35]. The role of RAS in the kidney of type 2 diabetic mice (db/db mice) in our study was consistent with those studies performed on the type 1 diabetic animal models [36, 37]. As vitamin D exerts a vital effect by binding to vitamin D receptor (VDR), which is widely expressed in various organs

and tissues including kidneys, we considered that VDR signaling may be a paramount modulator in the process of kidney injuries and therefore constructed the VDR knockout mice and performed a series of systematic studies. At first, our study found a significant elevation in renin gene expression in VDR-null mice [38, 39]. In *in vitro* experiments, we revealed that the direct inhibitory effect of 1,25(OH)2D3 on renin was mainly attributed to its ability to inhibit the transcription of the renin gene and consequently cut off the activation of the RAS [38, 39]. The results of our subsequent study revealed that the absence of VDR stimulated severe renal damage with marked tubular atrophy, interstitial fibrosis, and increased renin expression and Ang II accumulation in the obstructed kidney of mice after surgery of unilateral ureteral obstruction (UUO) [29].

In line with the *in vivo* studies, in the podocytes with the absence of VDR, the mRNA levels of angiotensinogen (AGT), renin, and Ang II type 1 receptor (AT1R) were significantly upregulated, displaying the activation of RAS and therefore exacerbating podocytes damage [40]. Vitamin D and its analogs also repressed the activation of RAS in other renal cells, such as HIV-induced tubular cell injury, high-glucose-induced mesangial cells, juxtaglomerular cells, and Ang II-induced primary tubular cells [41, 42].

Collectively, vitamin D might prevent kidney injury associated with SARS-CoV-2 infection by attenuating renal RAS as shown by an upregulation of ACE2 expression and downregulation of renin expression as well as a reduction in the production of Ang II locally in the kidney.

#### *2.2.2 Epithelial-mesenchymal transition (EMT)*

Researchers supported that in addition to the RAS imbalance caused by SARS-CoV-2 infection, the COVID-19 may also bring about the EMT, which has been reported as a major mechanism responsible for the abnormal accumulation of extracellular matrix (ECM). As reported, the accumulation of proteins and fibroblasts in ECM is a predominant factor in causing most kidney diseases [29]. It is believed that vitamin D could prevent kidney fibrosis by repressing the process of EMT [29].

As shown in recent research, calcitriol and paricalcitol (at equivalent doses of 1000 IU/kg) prevented the renal fibrosis in the 7/8 nephrectomy model within 4 weeks of treatment through the inhibition of EMT characterized by the changes of E-cadherin and Snail [43]. Similarly, type I and type III collagen, fibronectin, α-smooth muscle actin, and E-cadherin, which are the typical markers of EMT, were significantly regulated in UUO mice treated with paricalcitol, which therefore ameliorated renal interstitial fibrosis and preserved tubular epithelial integrity in obstructive nephropathy [44]. Furthermore, the *in vitro* experimental studies demonstrated that the isolated primary tubular cells from VDR-null mice showed a significant EMT process, which was reached by analyzing the abundance of landmark indicators of EMT [29]. Consistent with the conclusion drawn from the primary tubular cell study, paricalcitol treatment also profoundly suppressed EMT in the human renal proximal tubular epithelial cells [45].

Overall, EMT might be one of the key pathogenic pathways for COVID-19-induced kidney injury, and the inhibition of EMT by vitamin D analogs suggests that it may ameliorate renal injury *via* declining renal EMT caused by SARS-CoV-2 infection.

#### *2.2.3 Oxidative stress, inflammation, and cytokine storm*

As mentioned earlier, vitamin D is not only an essential factor for modulating real RAS and suppressing the EMT process, but also for regulating oxidative stress

## *Pharmacological Efficacy and Mechanism of Vitamin D in the Treatment of "Kidney-Brain"… DOI: http://dx.doi.org/10.5772/intechopen.105820*

and inhibiting inflammation and cytokine storm, consequently reducing COVID-19 induced kidney damage [26]. The SARS-CoV-2 infection triggers the massive production of reactive oxygen species (ROS) and promotes oxidative damage. Jain *et al*. [46] have proposed that ROS overproduction and excessive oxidative stress are responsible for impaired immunity, cytokine storm secretion, and the onset of organ dysfunction in response to COVID-19 infection. The insights could be interpreted as follows: for example, Wu *et al.* [47] revealed that cholecalciferol has the potential, as a clinical drug, to protect renal function in ischemia/reperfusion (I/R)-induced AKI by reducing ROS production and inhibiting oxidative stress. Other studies also suggested that vitamin D analogs could participate in the induction of intracellular free radical scavenging and attenuate kidney disorder through the downregulation of mTOR expression and autophagy-related oxidant response [48–50].

Low 25(OH)D status in COVID-19 patients was correlated with high levels of interleukin-6 (IL-6) and C-reactive protein (CRP), which are the independently inflammatory markers. Furthermore, the COVID-19 patients with insufficient 25(OH)D content may exert a high incidence of inflammation-induced renal injury [51]. Several experimental studies have reported that the administration of VDR activators reduced the presence of inflammatory cells in the kidney, thereby suppressing inflammatory responses and cytokine storms [7, 52–54]. Additionally, vitamin D intervention could decrease the production of inflammatory cytokines such as IL-6, IL-8, IL-12, IL-17, tumor necrosis factor-α (TNF-α), and interferons-γ (IFN-γ), and thus prevent inflammation from progressing and damaging other organs, including the kidneys [55–57]. As a result, numerous preclinical studies have been conducted using vitamin D as a treatment for various types of AKI, such as sepsis-induced AKI, with promising results in mitigating both renal oxidative stress and the expression of inflammatory cytokines in kidney [58].

Therefore, vitamin D could have the potential in diminishing the cytokine storm caused by COVID-19 and could exert protective effects against kidney injury.

#### *2.2.4 Immune response*

The active vitamin D molecule 1,25(OH)2D3 could be produced in the kidneys and in extrarenal tissues such as activated monocytes/macrophages, where VDR is also expressed and is therefore vitamin D targets as well [59, 60]. Various studies have shown a stimulatory effect of vitamin D on Tregs (CD4+ , CD25<sup>+</sup> , CD127− , FoxP3<sup>+</sup> ), which are the important immune response cells in humans [61–63].

In detail, a study by Yuan *et al.* [64] found that combined treatment with vitamin D and tacrolimus effectively alleviated renal tissue damage in rats with IgA nephropathy through modulating the immune response and the nuclear factor kappa-B/ toll-like receptor 4 (NF-κB/TLR4) pathway, the overactivation of which is a typical appearance of immune injury. Similar findings have been reported that 1,25(OH)2D3 protected against tubulointerstitial fibrosis by downregulating the innate immune NF-κB/TLR4 pathway in STZ (45 mg/kg)-induced diabetic rats with kidney disease and in high-glucose (25 mmol/L)-induced NRK-52E cells (a rat kidney tubular epithelial cell line) [65]. In addition, Penna *et al.* [66] demonstrated that the treatment of nonobese diabetes mice, a model of susceptible autoimmune disease, with a synthetic analog of 1,25(OH)2D3 could reduce IL-17 expression. Several studies also supported that vitamin D could play a role in the cross talk between innate and adaptive immunity in CKD patients, illustrating that vitamin D could improve organ damage, including kidney damage, by modulating the immune response [67–69].

Since SARS-CoV-2 infection affects the immune system first and foremost, vitamin D intervention could somehow regulate the body's immune function and the stress of immune cells in the kidney. Hence, it could be assumed that the modulations on the immune response might be one potential mechanism for the beneficial effects of vitamin D on kidney deterioration.

## **3. Vitamin D and CNS disorders**

## **3.1 Clinical practice**

As the current understanding of COVID-19 continues to evolve, accumulating evidence demonstrated the neurological impact of this novel virus [70], particularly, the term "NeuroCovid" has been proposed in 2020 [71]. During the acute phase of COVID-19, about 36% of cases developed neurological symptoms of which 25% could be attributed to the direct involvement of the central nervous system (CNS) [72]. Patients with neurological deficits such as Parkinson's disease (PD) did not exhibit an elevation in COVID-19 risk and mortality compared with the general population [73, 74]; however, COVID-19 might lead to the medium- and long-term consequences on CNS with neurodegenerative and neuropsychiatric diseases manifested as depression, insomnia, cognitive decline, accelerated aging, Parkinson's disease (PD), or Alzheimer's disease [71, 75]. The infection with SARS-CoV-2 even aggravates the CNS disorders and neurological complications of COVID-19 patients with preexisting neurological injury. In children with multiple sclerosis, the results of the web-based survey showed high anxiety levels during the pandemic [76]. Additionally, the affected patients associated with cognitive deficits might be at higher risk of cognitive decline after overcoming the COVID-19 infection [70]. Importantly, a systematic review of studies reporting data on PD patients with a diagnosis of COVID-19 indicated a higher case fatality in PD patients affected by COVID-19 than the general population [74]. Therefore, a strengthened awareness of the possibility of neurological involvement and a further investigation into the relevant pathophysiology would be essential to understand and ultimately abrogate SARS-CoV-2-related neurological symptoms [77].

An unselected large cohort study from Italy showed that the nonadvanced PD patients without vitamin D supplementation were more likely to be infected [73], and a retrospective survey from Spain elucidated that lower blood level of vitamin D was one of the main factors for developing COVID-19 in children with neuroimmunological disorders [78]. Consistently the systematic analysis including 16 studies reporting on a total of 11,325 PD patients suggested vitamin D might be a key protective factor against this infection [74], and the meta-analysis indicated the close correlation of vitamin D supplementation with COVID-19 in people with PD [79]. Furthermore, an early study using a multivariate general linear model found that a low serum level of 25(OH)D could predict an increased vulnerability to the stressful impact of the COVID-19 outbreak [80]. Collectively, vitamin D deficiency in circulation not only increases susceptibility to COVID-19 in patients with CNS disorders but also accelerates or aggravates preexisting neurodegenerative disease in COVID-19 patients.

Most of the emerging clinical results supported the beneficial effects of vitamin D supplements or therapy on neurological complications in COVID-19 patients, in accordance with the neuroprotective effects of vitamin D and its analogs. It is well elucidated that SARS-CoV-2 is a neuroinvasive virus capable of eliciting a cytokine

*Pharmacological Efficacy and Mechanism of Vitamin D in the Treatment of "Kidney-Brain"… DOI: http://dx.doi.org/10.5772/intechopen.105820*

storm, with persistent effects in specific populations. The impact of SARS-CoV-2 infection on the onset and progression of neurological diseases of neuroinflammatory origin is regarded as the potential cause of a delayed pandemic [81]. Remarkably, as a nonclassical role beyond action on skeletal homeostasis, the pharmacological regulations of vitamin D on inflammation responses including neuroinflammation have been widely studied. An interesting review stated that vitamin D could partially produce positive effects on the development of brain function for infants of mothers who experienced viral infections in early pregnancy by reducing some pro-inflammatory cytokines [82]. Vitamin D might act as a strong immunosuppressant repressing cytokine release syndrome in COVID-19 via attenuating the production and secretion of crucial pro-inflammatory cytokines including NF-kB, IL-6, IL-1β, and TNF [83]. One recent review implicated that the immunomodulatory effects of vitamin D significantly reduced the level of pro-inflammatory interleukins and enhanced the synthesis of anti-inflammatory chemical mediators [84]. Taken together, supplementation with vitamin D could be an effective option to avoid the development and progression of neurodegenerative pathologies in post-COVID-19 patients.

#### **3.2 Mechanism studies**

Given the extrarenal regulation of vitamin D on tissue function, its extrarenal metabolism, especially in CNS, will be extremely concerned in the research studies on neurological illnesses accompanied by COVID-19. Experimental data showed that VDR is expressed in CNS such as neurons and microglia, and 25(OH)D3 could be directly metabolized to 1,25(OH)2D3 due to the local presence of 1α-hydroxylase, implying a potential modulation of vitamin D in CNS in an autocrine or paracrine fashion. 1,25(OH)2D3 could stimulate the expression of glial cell line–derived neurotrophic factor, nerve growth factor, and neurotrophins-like nerve growth factor (NGF), thereby preventing loss of neural sensation in COVID-19 [83]. Moreover, 1,25(OH)2D3 could promote the expression of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin receptor p75NTR in neurons, glial cells, and Schwann cells [83], as well as induce the migration and differentiation of oligodendrocyte progenitors and enhance remyelination of neurons to improve neurotransmission in a model of toxic demyelination [85]. Additionally, it improved serotoninergic and dopaminergic neurotransmission in cultured neuronal cells by modulating serotonin and dopamine metabolism [86]. These effects account for the potential therapeutic efficacy of vitamin D on COVID-19-derived neuropsychiatric disorders [84].

Considering our previous work emphasized the role of RAS in the development of tissue injuries and the inhibitory effects of vitamin D on overactivity of tissue RAS, we attempted to uncover the underlying molecular mechanisms involved in the protection of vitamin D in COVID-19 patients from CNS damages on the aspect of brain RAS, which has been proposed five decades ago [87]. Human studies on the postmortem brain revealed that human coronavirus variants and SARS-CoV-2 could infect neurons and glia, demonstrating that SARS-CoV-2 may have similar neurovirulence [77]. In fact, the SARS-CoV-2 virus could use the ACE2 to cross the blood-brain barrier and invade neuronal and glial cells, as the studies have explored that SARS-CoV-2 has a high affinity for its receptor, the ACE2 protein [84, 88]. Furthermore, the research data showed the expression of ACE2 in neuronal and glial cells [89], which are also potentially vulnerable to SARS-CoV-2 infection. Attractively, a few studies have demonstrated the existence of RAS components in the basal ganglia, and particularly in the nigrostriatal system [90], even in mitochondria of dopaminergic neurons [91], though there are still controversial opinions about the presence of brain RAS as the angiotensin generation in the brain is concerned [87, 92].

It is well defined that there are two counterregulatory arms within RAS, namely the classical axis ACE/Ang II/AT1R and the newly emerged axis ACE2/Ang(1–7)/ Mas [93]. The identification of the ACE homolog, ACE2 as a key Ang(1–7)-forming enzyme, unravels the existence of a distinct enzymatic pathway for the production of Ang(1–7), which has a broad range of effects in different organs and tissues that goes beyond its initially described cardiovascular and renal actions [94]. The decline in ACE2 expression that occurs with aging has been associated with higher morbidity and mortality rates in older adults [95]. Furthermore, numerous studies discovered that the cross talk and the interaction between the dual-axis systems of RAS contribute to tissue homeostasis. Our research project entitled "Biological effect of the double axes within RAS, ACE/Ang II/AT1R and ACE2/Ang(1-7)/Mas, in bone metabolism disturbance induced by high glucose and intervention study of active components in kidney-tonifying TCM," funded by National Natural Science Foundation of China, illustrated that the two axes distinctly regulated the differentiation and functions of osteoblasts and osteoclasts upon exposure to high glucose [96]. Our study [96] and another study [97] support the concept that the ACE2/Ang(1–7)/Mas axis is able to counteract most of the deleterious actions of the ACE/Ang II/AT1R axis, especially in pathological conditions. Thus, we suppose that the interfering of SARS-CoV-2 with ACE2 in the brain would lead to a disturbance between the two axes and, in turn, produce deleterious effects in CNS observed in infected patients.

In vivo and in vitro studies clarified a counterregulatory interaction between dopamine and angiotensin receptors [98] and between SIRT3 and angiotensin receptors [99] in the striatum and substantia nigra, especially in an age-dependent manner, thereafter induced dopaminergic function injury accounting for the rise in the risk of neurodegenerative diseases, such as PD. Besides that, the hyperactivation of the ACE/Ang II/AT1R axis could exacerbate dopaminergic cell death, the animal study explicated that the Ang(1–7)/Mas axis possessed a neuroprotective role in the dopaminergic system, and in turn, ameliorated aging-related vulnerability to neurodegeneration [100].

Vitamin D could raise the bioavailability and upregulate the expression of ACE2, which may be responsible for trapping and inactivating SARS-CoV-2 [101, 102]. Importantly, vitamin D could mitigate the RAS-activation-evoked tissue destruction by serving as an RAS inhibitor. The overall effects of vitamin D on brain RAS are assumed as a drop-in Ang II level and a rise in Ang(1–7) level by inducing the ACE2/Ang(1–7)/Mas axis activity and suppressing ACE/Ang II/AT1R axis [88, 103]. Our research articles have reported that active vitamin D analog paricalcitol could dramatically improve LPS-induced depressive-like behavior of mice by abolishing neuroinflammation via diminishing RAS activity in the hypothalamus [104], and the kidney-tonifying traditional herb Fructus Ligustri Lucidi displayed the suppressive effects on levels of pro-inflammatory cytokines by improving vitamin D metabolism [105]. Consistent with these findings, vitamin D supplementation appeared to reverse COVID-19-related neurodegeneration and neuroinflammation, which are aggravated in Parkinson's and Alzheimer's patients [95]. These pieces of evidence heighten the key role of vitamin D as a neuroprotective and neuroreparative agent against the neurological sequelae of COVID-19.

Taken together, the mechanism studies revealed the crucial role of VDR in the protection of nephropathy through regulating multiple biological events (**Figure 1**) and that

*Pharmacological Efficacy and Mechanism of Vitamin D in the Treatment of "Kidney-Brain"… DOI: http://dx.doi.org/10.5772/intechopen.105820*

*Vitamin D displayed nephroprotective effects through regulating multiple biological events.*

**Figure 2.**

*Vitamin D exerted neuroprotective effects via, at least partially, modulating RAS homeostasis in CNS.*

vitamin D exerted neuroprotective effects by balancing RAS in CNS (**Figure 2**), thereby vitamin D and its analogs possess the high potential in the protection and treatment of kidney and CNS disorders associated with COVID-19.

## **Acknowledgements**

This chapter was supported in part by National Natural Science Foundation of China (82074468), Scientific and Innovative Action Plan from Science and

Technology Commission of Shanghai Municipality (21400760400), National Key R&D Program (2018YFC1704302) and Program for Innovative Research Team (2015RA4002) from Ministry of Science and Technology of China, and Shanghai Collaborative Innovation Center of Industrial Transformation of Hospital TCM Preparation.

## **Conflict of interest**

The authors declare no conflict of interest.

## **Author details**

Jia-Li Zhang, Yong-Jun Wang and Yan Zhang\* Shanghai University of Traditional Chinese Medicine, Longhua Hospital, Shanghai, China

\*Address all correspondence to: medicineyan@aliyun.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Pharmacological Efficacy and Mechanism of Vitamin D in the Treatment of "Kidney-Brain"… DOI: http://dx.doi.org/10.5772/intechopen.105820*

## **References**

[1] Mercola J, Grant WB, Wagner CL. Evidence regarding vitamin D and risk of COVID-19 and its severity. Nutrients. 2020;**12**(11):3361. DOI: 10.3390/ nu12113361

[2] Demir M, Demir F, Aygun H. Vitamin D deficiency is associated with COVID-19 positivity and severity of the disease. Journal of Medical Virology. 2021;**93**(5):2992-2999. DOI: 10.1002/ jmv.26832

[3] Papadimitriou DT, Vassaras AK, Holick MF. Association between population vitamin D status and SARS-CoV-2 related serious-critical illness and deaths: An ecological integrative approach. World Journal of Virology. 2021;**10**(3):111-129. DOI: 10.5501/wjv. v10.i3.111

[4] Ali N. Role of vitamin D in preventing of COVID-19 infection, progression and severity. Journal of Infection and Public Health. 2020;**13**(10):1373-1380. DOI: 10.1016/j.jiph.2020.06.021

[5] Zhao F, Yang Z, Wang N, et al. Traditional Chinese medicine and western medicine share similar philosophical approaches to fight COVID-19. Aging & Disease. 2021;**12**(5):1162- 1168. DOI: 10.14336/AD.2021.0512

[6] Jeon SR, Kang JW, Ang L, et al. Complementary and alternative medicine (CAM) interventions for COVID-19: An overview of systematic reviews. Integrative Medicine Research. 2022;**11**(3):100842. DOI: 10.1016/j. imr.2022.100842

[7] Zhang JL, Li WX, Li Y, et al. Therapeutic options of TCM for organ injuries associated with COVID-19 and the underlying mechanism.

Phytomedicine. 2021;**85**:153297. DOI: 10.1016/j.phymed.2020.153297

[8] Zhang Y, Dong XL, Leung PC, et al. Fructus Ligustri Lucidi extract improves calcium balance and modulates the calciotropic hormones level and vitamin D-dependent gene expression in aged ovariectomized rats. Menopause. 2008;**15**(3):558-565. DOI: 10.1097/ gme.0b013e31814fad27

[9] Zhang Y, Lai WP, Leung PC, et al. Improvement of Ca balance by Fructus Ligustri Lucidi extract in aged female rats. Osteoporosis International. 2008;**19**(2):235-242. DOI: 10.1007/ s00198-007-0442-9

[10] Zhang Y, Diao TY, Wang L, et al. Protective effects of water fraction of Fructus Ligustri Lucidi extract against hypercalciuria and trabecular bone deterioration in experimentally type 1 diabetic mice. Journal of Ethnopharmacology. 2014;**158**(Part A):239-245. DOI: 10.1016/j.jep.2014.10.025

[11] Liu M, Mei K, Tan Z, et al. Liver fibrosis scores and hospitalization, mechanical ventilation, severity, and death in patients with COVID-19: A systematic review and doseresponse meta-analysis. Canadian Journal of Gastroenterology and Hepatology. 2022;**2022**:7235860. DOI: 10.1155/2022/7235860

[12] Singh J, Malik P, Patel N, et al. Kidney disease and COVID-19 disease severitysystematic review and meta-analysis. Clinical and Experimental Medicine. 2022;**22**(1):125-135. DOI: 10.1007/ s10238-021-00715-x

[13] Yu JN, Wu BB, Yang J, et al. Cardio-cerebrovascular disease is associated with severity and mortality of COVID-19: A systematic review and meta-analysis. Biological Research for Nursing. 2021;**23**(2):258-269. DOI: 10.1177/1099800420951984

[14] Iaccarino G, Grassi G, Borghi C, et al. Age and multimorbidity predict death among COVID-19 patients: Results of the SARS-RAS study of the Italian society of hypertension. Hypertension. 2020;**76**(2):366-372. DOI: 10.1161/ HYPERTENSIONAHA.120.15324

[15] Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: A systematic review and meta-analysis. International Journal of Infectious Diseases. 2020;**94**:91-95. DOI: 10.1016/j.ijid.2020.03.017

[16] Bradley SA, Banach M, Alvarado N, et al. Prevalence and impact of diabetes in hospitalized COVID-19 patients: A systematic review and meta-analysis. Journal of Diabetes. 2022;**14**(2):144-157. DOI: 10.1111/1753-0407.13243

[17] Naicker S, Yang CW, Hwang SJ, et al. The novel coronavirus 2019 epidemic and kidneys. Kidney International. 2020;**97**(5):824-828. DOI: 10.1016/j. kint.2020.03.001

[18] Hirsch JS, Ng JH, Ross DW, et al. Acute kidney injury in patients hospitalized with COVID-19. Kidney International. 2020;**98**(1):209-218. DOI: 10.1016/j.kint.2020.05.006

[19] Chang TS, Ding Y, Freund MK, et al. Prior diagnoses and medications as risk factors for COVID-19 in a Los Angeles health system. medRxiv. 9 Jul 2020. DOI: 10.1101/2020.07.03.20145581

[20] Lu JY, Hou W, Duong TQ. Longitudinal prediction of hospitalacquired acute kidney injury in

COVID-19: A two-center study. Infection. 2022;**50**(1):109-119. DOI: 10.1007/s15010-021-01646-1

[21] Meltzer DO, Best TJ, Zhang H, et al. Association of vitamin D status and other clinical characteristics with COVID-19 test results. JAMA Network Open. 2020;**3**(9):e2019722. DOI: 10.1001/ jamanetworkopen.2020.19722

[22] Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clinical and Experimental Research. 2020;**32**(7):1195- 1198. DOI: 10.1007/s40520-020-01570-8

[23] D'Avolio A, Avataneo V, Manca A, et al. 25-Hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2. Nutrients. 2020;**12**(5):1359. DOI: 10.3390/ nu12051359

[24] Alcala-Diaz JF, Limia-Perez L, Gomez-Huelgas R, et al. Calcifediol treatment and hospital mortality due to COVID-19: A cohort study. Nutrients. 2021;**13**(6):1760. DOI: 10.3390/ nu13061760

[25] Rastogi A, Bhansali A, Khare N, et al. Short term, high-dose vitamin D supplementation for COVID-19 disease: A randomised, placebo-controlled, study (SHADE study). Postgraduate Medical Journal. 2022;**98**(1156):87-90. DOI: 10.1136/postgradmedj-2020-139065

[26] Ding R, Xiao Z, Jiang Y, et al. Calcitriol ameliorates damage in highsalt diet-induced hypertension: Evidence of communication with the gut-kidney axis. Experimental Biology and Medicine (Maywood). 2022;**247**(8):624-640. DOI: 10.1177/15353702211062507

[27] Farid N, Rola N, Koch EAT, et al. Active vitamin D supplementation

*Pharmacological Efficacy and Mechanism of Vitamin D in the Treatment of "Kidney-Brain"… DOI: http://dx.doi.org/10.5772/intechopen.105820*

and COVID-19 infections: Review. Irish Journal of Medical Science. 2021;**190**(4):1271-1274. DOI: 10.1007/ s11845-020-02452-8

[28] Tylicki L, Puchalska-Reglińska E, Tylicki P, et al. Predictors of mortality in hemodialyzed patients after SARS-CoV-2 infection. Journal of Clinical Medicine. 2022;**11**(2):285. DOI: 10.3390/ jcm11020285

[29] Zhang Y, Kong J, Deb DK, et al. Vitamin D receptor attenuates renal fibrosis by suppressing the reninangiotensin system. Journal of The American Society of Nephrology. 2010;**21**(6):966-973. DOI: 10.1681/ ASN.2009080872

[30] Li YC. Vitamin D regulation of the renin-angiotensin system. Journal of Cellular Biochemistry. 2003;**88**(2): 327-331. DOI: 10.1002/jcb.10343

[31] Yuste C, Quiroga B, de Vinuesa SG, et al. The effect of some medications given to CKD patients on vitamin D levels. Nefrología. 2015;**35**(2):150-156. DOI: 10.1016/j.nefro.2015.05.016

[32] de Almeida LF, Coimbra TM. When less or more isn't enough: Renal maldevelopment arising from disequilibrium in the reninangiotensin system. Frontiers in Pediatrics. 2019;**7**:296. DOI: 10.3389/ fped.2019.00296

[33] Zhang Y, Deb DK, Kong J, et al. Long-term therapeutic effect of vitamin D analog doxercalciferol on diabetic nephropathy: Strong synergism with AT1 receptor antagonist. The American Journal of Physiology-Renal Physiology. 2009;**297**(3):F791-F801. DOI: 10.1152/ ajprenal.00247.2009

[34] Zhang Z, Zhang Y, Ning G, et al. Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase. Proceedings of the National Academy of Sciences of the United States of America. 2008;**105**(41):15896-15901. DOI: 10.1073/pnas.0803751105

[35] Deng X, Cheng J, Shen M. Vitamin D improves diabetic nephropathy in rats by inhibiting renin and relieving oxidative stress. Journal of Endocrinological Investigation. 2016;**39**(6):657-666. DOI: 10.1007/s40618-015-0414-4

[36] Wang Y, Zhou J, Minto AW, et al. Altered vitamin D metabolism in type II diabetic mouse glomeruli may provide protection from diabetic nephropathy. Kidney International. 2006;**70**(5):882- 891. DOI: 10.1038/sj.ki.5001624

[37] Zhang Y, Li XL, Sha NN, et al. Differential response of bone and kidney to ACEI in db/db mice: A potential effect of captopril on accelerating bone loss. Bone. 2017;**97**:222-232. DOI: 10.1016/j. bone.2017.01.029

[38] Li YC, Kong J, Wei M, et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. The Journal of Clinical Investigation. 2002;**110**(2):229- 238. DOI: 10.1172/JCI15219

[39] Li YC, Qiao G, Uskokovic M, et al. Vitamin D: A negative endocrine regulator of the renin-angiotensin system and blood pressure. The Journal of Steroid Biochemistry and Molecular Biology. 2004;**89-90**(1-5):387-392. DOI: 10.1016/j.jsbmb.2004.03.004

[40] Chandel N, Ayasolla K, Wen H, et al. Vitamin D receptor deficit induces activation of renin angiotensin system via SIRT1 modulation in podocytes. Experimental and Molecular Pathology. 2017;**102**(1):97-105. DOI: 10.1016/j. yexmp.2017.01.001

[41] Salhan D, Husain M, Subrati A, et al. HIV-induced kidney cell injury: Role of ROS-induced downregulated vitamin D receptor. The American Journal of Physiology-Renal Physiology. 2012;**303**(4):F503-F514. DOI: 10.1152/ ajprenal.00170.2012

[42] Zhang Z, Sun L, Wang Y, et al. Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney International. 2008;**73**(2):163-171. DOI: 10.1038/sj.ki.5002572

[43] Martínez-Arias L, Panizo S, Alonso-Montes C, et al. Effects of calcitriol and paricalcitol on renal fibrosis in CKD. Nephrology Dialysis Transplantation. 2021;**36**(5):793-803. DOI: 10.1093/ndt/gfaa373

[44] Tan X, Li Y, Liu Y. Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy. Journal of The American Society of Nephrology. 2006;**17**(12):3382-3393. DOI: 10.1681/ ASN.2006050520

[45] Kim CS, Joo SY, Lee KE, et al. Paricalcitol attenuates 4-hydroxy-2 hexenal-induced inflammation and epithelial-mesenchymal transition in human renal proximal tubular epithelial cells. PLoS One. 2013;**8**(5):e63186. DOI: 10.1371/journal.pone.0063186

[46] Jain SK, Parsanathan R, Levine SN, et al. The potential link between inherited G6PD deficiency, oxidative stress, and vitamin D deficiency and the racial inequities in mortality associated with COVID-19. Free Radical Biology and Medicine. 2020;**161**:84-91. DOI: 10.1016/j. freeradbiomed.2020.10.002

[47] Wu W, Liu D, Zhao Y, et al. Cholecalciferol pretreatment ameliorates ischemia/reperfusion-induced acute kidney injury through inhibiting ROS production, NF-κB pathway

and pyroptosis. Acta Histochemica. 2022;**124**(4):151875. DOI: 10.1016/j. acthis.2022.151875

[48] Lee H, Lee H, Lim Y. Vitamin D3 improves lipophagy-associated renal lipid metabolism and tissue damage in diabetic mice. Nutrition Research. 2020;**80**:55-65. DOI: 10.1016/j.nutres.2020.06.007

[49] Khodir SA, Samaka RM, Ameen O. Autophagy and mTOR pathways mediate the potential renoprotective effects of vitamin D on diabetic nephropathy. International Journal of Nephrology. 2020;**2020**:7941861. DOI: 10.1155/2020/7941861

[50] Mitrašinović-Brulić M, Dervišević A, Začiragić A, et al. Vitamin D3 attenuates oxidative stress and regulates glucose level and leukocyte count in a semichronic streptozotocin-induced diabetes model. Journal of Diabetes & Metabolic Disorders. 2021;**20**(1):771-779. DOI: 10.1007/s40200-021-00814-2

[51] Campi I, Gennari L, Merlotti D, et al. Vitamin D and COVID-19 severity and related mortality: A prospective study in Italy. BMC Infectious Disease. 2021;**21**(1):566. DOI: 10.1186/ s12879-021-06281-7

[52] Panichi V, Migliori M, Taccola D, et al. Effects of 1,25(OH)2D3 in experimental mesangial proliferative nephritis in rats. Kidney International. 2001;**60**(1):87-95. DOI: 10.1046/j.1523-1755.2001.00775.x

[53] Tan X, Wen X, Liu Y. Paricalcitol inhibits renal inflammation by promoting vitamin D receptor-mediated sequestration of NF-κB signaling. Journal of The American Society of Nephrology. 2008;**19**(9):1741-1752. DOI: 10.1681/ ASN.2007060666

[54] Trivedi MK, Mondal S, Gangwar M, et al. Effects of cannabidiol interactions

*Pharmacological Efficacy and Mechanism of Vitamin D in the Treatment of "Kidney-Brain"… DOI: http://dx.doi.org/10.5772/intechopen.105820*

with CYP2R1, CYP27B1, CYP24A1, and vitamin D3 receptors on spatial memory, pain, inflammation, and aging in vitamin D3 deficiency diet-induced rats. Cannabis and Cannabinoid Research. 19 Apr 2022. DOI: 10.1089/can.2021.0240

[55] Palmer MT, Lee YK, Maynard CL, et al. Lineage-specific effects of 1,25-dihydroxyvitamin D(3) on the development of effector CD4 T cells. Journal of Biological Chemistry. 2011;**286**(2):997-1004. DOI: 10.1074/jbc. M110.163790

[56] Talmor Y, Bernheim J, Klein O, et al. Calcitriol blunts pro-atherosclerotic parameters through NF-κB and p38 *in vitro*. European Journal of Clinical Investigation. 2008;**38**(8):548-554. DOI: 10.1111/j.1365-2362.2008.01977.x

[57] Tsoukas CD, Provvedini DM, Manolagas SC. 1,25-Dihydroxyvitamin D3: A novel immunoregulatory hormone. Science. 1984;**224**(4656):1438-1440. DOI: 10.1126/science.6427926

[58] LaFavers K. Disruption of kidneyimmune system crosstalk in sepsis with acute kidney injury: Lessons learned from animal models and their application to human health. International Journal of Molecular Sciences. 2022;**23**(3):1702. DOI: 10.3390/ ijms23031702

[59] Arora J, Wang J, Weaver V, et al. Novel insight into the role of the vitamin D receptor in the development and function of the immune system. The Journal of Steroid Biochemistry and Molecular Biology. 2022;**219**:106084. DOI: 10.1016/j.jsbmb.2022.106084

[60] Hsu CH, Patel SR, Young EW, et al. The biological action of calcitriol in renal failure. Kidney International. 1994;**46**(3):605-612. DOI: 10.1038/ ki.1994.312

[61] Fraga M, Yáñez M, Sherman M, et al. Immunomodulation of T helper cells by tumor microenvironment in oral cancer is associated with CCR8 expression and rapid membrane vitamin D signaling pathway. Frontiers in Immunology. 2021;**12**:643298. DOI: 10.3389/ fimmu.2021.643298

[62] Wang Y, Zheng J, Islam MS, et al. The role of CD4<sup>+</sup> FoxP3+ regulatory T cells in the immunopathogenesis of COVID-19: Implications for treatment. International Journal of Biological Sciences. 2021;**17**(6):1507-1520. DOI: 10.7150/ ijbs.59534

[63] Lamikanra AA, Tsang HP, Elsiddig S, et al. The migratory properties and numbers of T regulatory cell subsets in circulation are differentially influenced by season and are associated with vitamin D status. Frontiers in Immunology. 2020;**11**:685. DOI: 10.3389/ fimmu.2020.00685

[64] Yuan D, Fang Z, Sun F, et al. Effect of vitamin D and tacrolimus combination therapy on IgA nephropathy. Medical Science Monitor. 2017;**23**:3170-3177. DOI: 10.12659/msm.905073

[65] Liu P, Li F, Xu X, et al. 1,25(OH)2D3 provides protection against diabetic kidney disease by downregulating the TLR4-MyD88-NF-κB pathway. Experimental and Molecular Pathology. 2020;**114**:104434. DOI: 10.1016/j. yexmp.2020.104434

[66] Penna G, Amuchastegui S, Cossetti C, et al. Treatment of experimental autoimmune prostatitis in nonobese diabetic mice by the vitamin D receptor agonist elocalcitol. The Journal of Immunology. 2006;**177**(12):8504-8511. DOI: 10.4049/jimmunol.177.12.8504

[67] Bock G, Prietl B, Mader JK, et al. The effect of vitamin D supplementation on peripheral regulatory T cells and β cell function in healthy humans: A randomized controlled trial. Diabetes/ Metabolism Research and Reviews. 2011;**27**(8):942-945. DOI: 10.1002/ dmrr.1276

[68] Wang H, He X, Liang S, et al. Role of vitamin D in ulcerative colitis: An update on basic research and therapeutic applications. Expert Review of Gastroenterology and Hepatology. 2022;**16**(3):251-264. DOI: 10.1080/17474124.2022.2048817

[69] Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;**126**(6):1121-1133. DOI: 10.1016/j.cell.2006.07.035

[70] Heneka MT, Golenbock D, Latz E, et al. Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. Alzheimer's Research & Therapy. 2020;**12**(1):69. DOI: 10.1186/ s13195-020-00640-3

[71] Fotuhi M, Mian A, Meysami S, et al. Neurobiology of COVID-19. Journal of Alzheimer's Disease. 2020;**76**(1):3-19. DOI: 10.3233/JAD-200581

[72] Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurology. 2020;**77**(6):683-690. DOI: 10.1001/jamaneurol.2020.1127

[73] Fasano A, Cereda E, Barichella M, et al. COVID-19 in Parkinson's disease patients living in lombardy, Italy. Movement Disorders. 2020;**35**(7):1089- 1093. DOI: 10.1002/mds.28176

[74] Artusi CA, Romagnolo A, Ledda C, et al. COVID-19 and Parkinson's disease: What do we know so far? Journal of Parkinson's Disease. 2021;**11**(2):445-454. DOI: 10.3233/JPD-202463

[75] Morkavuk G, Demirkol A, Berber GE, et al. Comparison of dementia patients admission rates and dementia characteristics before and during the COVID-19 pandemic. Cureus. 2021;**13**(11):e19934. DOI: 10.7759/ cureus.19934

[76] Dilek TD, Boybay Z, Kologlu N, et al. The impact of SARS-CoV2 on the anxiety levels of subjects and on the anxiety and depression levels of their parents. Multiple Sclerosis and Related Disorders. 2021;**47**:102595. DOI: 10.1016/j. msard.2020.102595

[77] Aghagoli G, Gallo Marin B, Katchur NJ, et al. Neurological involvement in COVID-19 and potential mechanisms: A review. Neurocritical Care. 2021;**34**(3):1062-1071. DOI: 10.1007/s12028-020-01049-4

[78] Olivé-Cirera G, Fonseca E, Cantarín-Extremera V, et al. Impact of COVID-19 in immunosuppressed children with neuroimmunologic disorders. Neurology Neuroimmunology & Neuroinflammation. 2021;**9**(1):e1101. DOI: 10.1212/NXI.0000000000001101

[79] Chambergo-Michilot D, Barros-Sevillano S, Rivera-Torrejón O, et al. Factors associated with COVID-19 in people with Parkinson's disease: A systematic review and meta-analysis. European Journal of Neurology. 2021;**28**(10):3467-3477. DOI: 10.1111/ ene.14912

[80] Di Nicola M, Dattoli L, Moccia L, et al. Serum 25-hydroxyvitamin D levels and psychological distress symptoms in patients with affective disorders during the COVID-19 pandemic. Psychoneuroendocrinology.

*Pharmacological Efficacy and Mechanism of Vitamin D in the Treatment of "Kidney-Brain"… DOI: http://dx.doi.org/10.5772/intechopen.105820*

2020;**122**:104869. DOI: 10.1016/j. psyneuen.2020.104869

[81] Serrano-Castro PJ, Estivill-Torrús G, Cabezudo-García P, et al. Impact of SARS-CoV-2 infection on neurodegenerative and neuropsychiatric diseases: A delayed pandemic? Neurología (English Edition). 2020;**35**(4):245-251. DOI: 10.1016/j. nrl.2020.04.002

[82] Hoffman MC, Freedman R, Law AJ, et al. Maternal nutrients and effects of gestational COVID-19 infection on fetal brain development. Clinical Nutrition ESPEN. 2021;**43**:1-8. DOI: 10.1016/j.clnesp.2021.04.019

[83] Xu Y, Baylink DJ, Chen CS, et al. The importance of vitamin D metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19. Journal of Translational Medicine. 2020;**18**(1): 322. DOI: 10.1186/s12967-020-02488-5

[84] Menéndez SG, Martín Giménez VM, Holick MF, et al. COVID-19 and neurological sequelae: Vitamin D as a possible neuroprotective and/ or neuroreparative agent. Life Sciences. 2022;**297**:120464. DOI: 10.1016/j. lfs.2022.120464

[85] Gomez-Pinedo U, Cuevas JA, Benito-Martín MS, et al. Vitamin D increases remyelination by promoting oligodendrocyte lineage differentiation. Brain and Behavior. 2020;**10**(1):e01498. DOI: 10.1002/brb3.1498

[86] Sabir MS, Haussler MR, Mallick S, et al. Optimal vitamin D spurs serotonin: 1,25-Dihydroxyvitamin D represses serotonin reuptake transport (SERT) and degradation (MAO-A) gene expression in cultured rat serotonergic neuronal cell lines. Genes and Nutrition. 2018;**13**:19. DOI: 10.1186/s12263-018-0605-7

[87] Cruz-López EO, Uijl E, Danser AHJ. Fifty years of research on the brain renin-angiotensin system: What have we learned? Clinical Science (Lond). 2021;**135**(14):1727-1731. DOI: 10.1042/ CS20210579

[88] Malek MA. A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19. Reviews in Medical Virology. 2020;**30**(5):e2119. DOI: 10.1002/rmv.2119

[89] Barrantes FJ. Central nervous system targets and routes for SARS-CoV-2: Current views and new hypotheses. ACS Chemical Neuroscience. 2020;**11**(18):2793-2803. DOI: 10.1021/ acschemneuro.0c00434

[90] Labandeira-García JL, Garrido-Gil P, Rodriguez-Pallares J, et al. Brain reninangiotensin system and dopaminergic cell vulnerability. Frontiers in Neuroanatomy. 2014;**8**:67. DOI: 10.3389/ fnana.2014.00067

[91] Valenzuela R, Costa-Besada MA, Iglesias-Gonzalez J, et al. Mitochondrial angiotensin receptors in dopaminergic neurons. Role in cell protection and aging-related vulnerability to neurodegeneration. Cell Death & Disease. 2016;**7**(10):e2427. DOI: 10.1038/ cddis.2016.327

[92] Uijl E, Ren L, Danser AHJ. Angiotensin generation in the brain: A re-evaluation. Clinical Science (Lond). 2018;**132**(8):839-850. DOI: 10.1042/ CS20180236

[93] Passos-Silva DG, Verano-Braga T, Santos RA. Angiotensin-(1-7): Beyond the cardio-renal actions. Clinical Science (Lond). 2013;**124**(7):443-456. DOI: 10.1042/CS20120461

[94] Santos RA, Ferreira AJ, Verano-Braga T, et al. Angiotensin-converting enzyme 2, angiotensin-(1-7) and mas: New players of the renin-angiotensin system. Journal of Endocrinology. 2013;**216**(2):R1-R17. DOI: 10.1530/ JOE-12-0341

[95] de Barros Viana M, Rosário BDA, de Fátima Santana de Nazaré M, et al. COVID-19 in age-related neurodegenerative diseases: Is there a role for vitamin D3 as a possible therapeutic strategy? Annual Review of Neuroscience. 2020;**32**(2):235-247. DOI: 10.1515/revneuro-2020-0074

[96] Sha NN, Zhang JL, Poon CC, et al. Differential responses of bone to angiotensin II and angiotensin(1-7): Beneficial effects of ANG(1-7) on bone with exposure to high glucose. American Journal of Physiology-Endocrinology and Metabolism. 2021;**320**(1):E55-E70. DOI: 10.1152/ajpendo.00158.2020

[97] Wong TP, Ho KY, Ng EK, et al. Upregulation of ACE2-ANG-(1-7) mas axis in jejunal enterocytes of type 1 diabetic rats: Implications for glucose transport. American Journal of Physiology-Endocrinology and Metabolism. 2012;**303**(5):E669-E681. DOI: 10.1152/ajpendo.00562.2011

[98] Villar-Cheda B, Dominguez-Meijide A, Valenzuela R, et al. Aging-related dysregulation of dopamine and angiotensin receptor interaction. Neurobiology of Aging. 2014;**35**(7):1726-1738. DOI: 10.1016/j. neurobiolaging.2014.01.017

[99] Diaz-Ruiz C, Villar-Cheda B, Dominguez-Meijide A, et al. Agingrelated overactivity of the angiotensin/ AT1 axis decreases Sirtuin 3 levels in the substantia nigra, which induces vulnerability to oxidative stress and neurodegeneration. The Journals of Gerontology. Series A-Biological Sciences and Medical Sciences.

2020;**75**(3):416-424. DOI: 10.1093/ gerona/gly259

[100] Costa-Besada MA, Valenzuela R, Garrido-Gil P, et al. Paracrine and intracrine angiotensin 1-7/mas receptor axis in the substantia nigra of rodents, monkeys, and humans. Molecular Neurobiology. 2018;**55**(7):5847-5867. DOI: 10.1007/s12035-017-0805-y

[101] Getachew B, Tizabi Y. Vitamin D and COVID-19: Role of ACE2, age, gender, and ethnicity. Journal of Medical Virology. 2021;**93**(9):5285-5294. DOI: 10.1002/jmv.27075

[102] Peng MY, Liu WC, Zheng JQ, et al. Immunological aspects of SARS-CoV-2 infection and the putative beneficial role of vitamin-D. International Journal of Molecular Sciences. 2021;**22**(10):5251. DOI: 10.3390/ijms22105251

[103] Mansur JL, Tajer C, Mariani J, et al. Vitamin D high doses supplementation could represent a promising alternative to prevent or treat COVID-19 infection. Clínica e Investigación en Arteriosclerosis. 2020;**32**(6):267-277. DOI: 10.1016/j.arteri.2020.05.003

[104] He MC, Shi Z, Sha NN, et al. Paricalcitol alleviates lipopolysaccharideinduced depressive-like behavior by suppressing hypothalamic microglia activation and neuroinflammation. Biochemical Pharmacology. 2019;**163**:1-8. DOI: 10.1016/j.bcp.2019.01.021

[105] Feng R, He MC, Li Q, et al. Phenol glycosides extract of Fructus Ligustri Lucidi attenuated depressivelike behaviors by suppressing neuroinflammation in hypothalamus of mice. Phytotherapy Research. 2020;**34**(12):3273-3286. DOI: 10.1002/ ptr.6777

## *Edited by Julia Fedotova*

Vitamin D is a unique bioregulatory molecule that can be synthesized in the skin as well as obtained via dietary sources. Vitamin D and its specific role in numerous diseases is a hot topic of scientific research. This book presents new insights into the specific role of vitamin D deficiency in the pathophysiological and biochemical mechanisms of many diseases. It is organized into four sections that present the latest data from clinical and preclinical investigations of the consequences of vitamin D deficiency in children and in diseases such as COVID-19 as well as cardiovascular, metabolic, endocrine, and renal disorders.

Published in London, UK © 2023 IntechOpen © Yuliia Bilousova / iStock

Vitamin D Deficiency - New Insights

Vitamin D Deficiency

New Insights

*Edited by Julia Fedotova*