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, 9, 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,”
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, 12, 13, 14, 15, 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
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 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 line with the
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
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
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 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
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, 53, 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, 56, 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+, CD127−, FoxP3+), which are the important immune response cells in humans [61, 62, 63].
In detail, a study by Yuan
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 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 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.
Acknowledgments
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.
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