The Dopamine System: Insights Between Kidney And Brain Ⅲ

Modifications of Brain DA in Animal Models 

The reduction of renal filtration in CKD leads to an accumulation of the solutes that would normally be excreted in the blood: the uremic toxins. The latter may be related to neurological manifestations [124]. In 2012, 146 uremic retention solutes were identified by the European Uremic Toxin Work Group (EUTox) (http://www.uremic-toxins.org/), classified into small water-soluble compounds, protein-bound compounds, and intermediate molecules (peptides) in patients with CKD.

Several animal models of CKD are available for the study of uremic toxins and brain effects. A few of them have been tested for cognitive performance and DA system. Here, we will briefly discuss data from the following models of CKD: (i) 5/6 nephrectomy, (ii) adenine-rich diet, (iii) DOCA-salt hypertensive animals, (iv) doxorubicin injection, (v) diabetic animals, (vi) BBS animal models. Furthermore, (vii) we will shortly discuss the effects of uremic toxins injected in animal models on DA neurons.

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1. Kidney nephrectomy has little effect on brain norepinephrine, DA, or serotonin [125]. However, brain synaptosomes from animals with kidney nephrectomy showed lower Vmax of tyrosine hydroxylase (TH), the enzyme rate-limiting step for DA synthesis [126]. Furthermore, animals with nephrectomy show an alteration of brain activity (indexed by cFOS expression) in the SN, where DA neurons are present [127]. At variance, nephrectomized mice showed significantly increased brain norepinephrine and DA [128]. 

2. Adenine-rich diet, a model of CKD, did not modify TH staining in the mesencephalon and in the striatum [129]. 

3. DOCA-salt and renal hypertensive rats showed slightly decreased activities of TH and DA-beta-hydroxylase in the brain [130]. 

4. A single injection of doxorubicin (a model of CKD) produced inhibition of DA system activity particularly in the hippocampus, with possible disturbances of the cognitive functions [131]. 

5. Animal models of pre-diabetes such as PED/PEA transgenic and Prep1 KO mice develop a form of Parkinson-like syndrome [102, 103] and modifications in a dopaminergic subsystem, that is, the olfactory system [106], as it happens in olfactory deficits observed in both PD [107, 108] and CKD [109]. 

6. BBS mutation leads to kidney disease cognitive impairment and altered trafficking of DA receptors [121– 123]. 

7. Homocysteine, an important uremic toxin [132], is also one of the degradation products of DA [133]. In the stripatal astrocytic processes of adult rats, the adenosine (A2A) and DA (D2) receptors can interact to form the A2A-D2 complex modulating the release of glutamate. Indeed, it has been shown that, in addition to inhibition of A2A activation, plasma homocysteine can also inhibit the effect of the DA D2 receptors [134]. Indoxyl sulfate (IS), another uremic toxin [135], also accumulates in the brain crossing the BBB due to an alteration of the organic anion transporter 3 [136]. IS contributes to the perturbation of CNS homeostasis and neuronal damage through mechanisms that increase inflammation and oxidative stress in glial cells [137]. Rats treated with IS showed alterations in the monoaminergic system and cognitive impairments [129, 138]. Chronic IS exposure led to alterations in DA concentration with a worsening in motor activity and spatial memory due to increased sensitivity to stress [138].

CKD and Brain DA: The Role of Ca and Trace Elements 

CKD is accompanied by brain diseases involving the DA neurons. Indeed, patients with CKD have an increased risk of PD (characterized by the loss of mesencephalic DA neurons) [139]. Furthermore, a DA deficiency is responsible for cognitive impairment [140]. However, the link between CKD and DA neurons is unclear and might be a consequence of several electrolytes, trace elements, and molecules accumulating in CKD.

Indeed, CKD is accompanied by several complications. Among these, vitamin D deficiency and hyperparathyroidism are common, with consequent alteration of the Ca and phosphorus metabolism. Furthermore, CKD patients may accumulate trace elements (aluminum [141], manganese, copper) [142, 143] in brain regions. Parathyroid hormone (PTH) elevation is weakly correlated to cognitive decline in the population with primary hyperparathyroidism [144]. At present, there is no link between PTH and DA neurons. However, PTH levels are correlated to plasma Ca levels, which might be implicated in cognitive deficit, as discussed below.

Conversely, a reduction in vitamin D is associated with cognitive impairment [145], its supplementation possibly improves cognition [146], although genetic studies do not confirm this link [147]. Furthermore, in animal models, vitamin D is neuroprotective for DA neurons [148]. Therefore, a vitamin D decrease in CKD might cause a dopaminergic dysfunction. The correction of vitamin D deficiency in CKD (using cholecalciferol or similar treatments) may lead to high plasma Ca levels (particularly in the presence of high PTH). Case reports show that elevated plasma Ca levels are linked to cognitive impairment, and its treatment with cinacalcet (in the case of elevated PTH) reverses the impairment [149]. Furthermore, elevated Ca can be undesirable for the risk of brain vascular calcifications, particularly in the presence of high phosphate.

In the past, isolated cases of end-stage kidney disease presented with aluminum accumulation in bone, brain, and other tissues, possibly deriving from aluminum-contraining drugs or contaminated dialysis water [142]. This was thought to be responsible for a neurological syndrome called "dialysis encephalopathy" or "dialysis dementia" [14, 141] and possibly in neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, and PD [150]. It was also proposed that aluminum may cause brain dysfunction by dysregulation of catecholamine neurotransmission including DA [151], although not by direct binding [152]. Another mineral, often less considered, which may accumulate in patients with CKD is manganese [143]. The excess of manganese can be neurotoxic to humans, affecting specific areas of the CNS including the basal ganglia, causing the appearance of extrapyramidal symptoms suggesting degeneration of dopaminergic neurons [153].

CKD and Brain DA: The Role of Uric Acid 

Uric acid is a very interesting chapter in the relationships between CKD and dopaminergic dysfunction. Since about 70% of uric acid is excreted by the kidneys, hyperuricemia occurs when kidney function deteriorates. It is unlikely that hyperuricemia plays a role in the progression of kidney disease. Serum uric acid is associated with the onset of hypertension in hyperuricemic patients. Hyhyperuricemia is associated with CKD, and it is a risk factor for renal failure in the general population; it is also a poor prognostic factor of renal function in IgA nephropathy [154].

Uric acid is correlated to the micro-architecture of renal tubular cells [116]. These cells show peculiar aspects such as the expression of high levels of the UCP2 protein, involved in mitochondrial uncoupling. The expression of UCP2 in proximal tubular cells may explain their relative propensity to damage in pathological conditions including hypertensive disease [155], which can be caused by hyperuricemia [156]. These tubule cells have a unique metabolic regulating system: in addition to UCP2, they also host a DPP-4 enzyme [157], responsible for degrading incretins, chemokines, hematopoietic growth factors, and neuropeptides [158]. They can be replaced by stem cells [159], a population of immature cells that are present in most tissues such as cartilage [160], bone marrow, and brain [161]. Considering the complex role of these tubular cells, it is not surprising that the increase of uric acid is one of the first symptoms of CKD.

Uric acid levels appear to have a U-shaped function relationship with brain functions. High levels of uric acid may cause vascular dementia [162], whereas low levels may cause Alzheimer's and Parkinson's dementia [162]. At present, it is unclear whether hypouricemia induced by high doses of hypouricemic drugs (e.g., allopurinol) in CKD may favor DA neuron degeneration, particularly considering the antioxidant and neuroprotective role of this substance [115, 163].

Peripheral Action of DA and the Role of Vasopressin 

DA also has an important peripheral action in addition to regulating various central functions. It has a clear influence on eGFR. Indeed, in patients with kidney failure, dopaminergic drugs also have a positive effect on renal function, causing a decrease in creatinine blood levels and an increase in GFR. A positive effect of selective D1 agonists (in particular, Fenoldopam) has been shown [164]. The mechanisms are unclear but, according to a recent study, selective D1 receptor agonists should be able to downregulate the expression of the nlrp3 gene that encodes an inflammasome protein. Furthermore, they would be able to reduce the inflammatory infiltrate in the kidney and the production of inflammatory cytokines (TNF-a, IL6, IL1b) allowing an increase in kidney function [165]. Interestingly, nlrp3 is more expressed in subjects with diabetic nephropathy, so its downregulation could delay renal damage in diabetic subjects [166]. 

Furthermore, DA can increase renal filtrate, through the vasodilation of the renal artery in patients with insufficient cardiac output and advanced heart failure [167]. It is easy to understand that CKD patients have a vicious circle that involves dopaminergic dysfunction and worsening renal function. The increase in eGFR caused by DA is called "renal reserve" and is a mechanism that DA works in concert with other substances including several amino acids present in the diet and vasopressin, the antidiuretic hormone produced by the hypothalamus and secreted by the posterior pituitary gland [168]. It has been seen that, among the various functions of vasopressin, there is that of increasing the release of DA from dopaminergic neurons [169]. Even DA can cause an increase in vasopressin levels [170]. This is interesting because, in light of recent studies, the alteration of the eGFR is not only due to a mere decrease in the number of glomeruli but also due to functional alterations [171]. In this context, dopamine dysfunction could be important. Among the less-known functions of vasopressin in the kidney, the regulation of Ca secretion in the tubules which according to recent studies is increased when the levels of the antidiuretic hormone are low [172]. This alteration of Ca homeostasis might also be relevant for hypercalciuric syndromes such as kidney stones [173].

DA Drugs and Kidney Disease 

Dopaminergic agonists are used for the treatment of PD [174] and other disorders that often accompany CKD, such as restless legs syndrome (RLS) [175]. Indeed, DA agonist drugs are indicated for some of the neuro-logical complications of CKD such as RLS and sleep disturbances [176, 177]. Among the drugs used to treat these complications, pramipexole, an agonist targeting the DA D3 receptor, is the one that appears to have the greatest efficacy in the treatment of RLS [178]. Therefore, DA neuron dysfunction might be implicated in this frequent neurological dysfunction of CKD. Further studies are needed to evaluate the effectiveness of DA agonists on cognitive impairment in CKD patients. 

Conclusions 

DA mediates both motor functions and cognitive functions, and this stems from its effects on dendritic spines in large brain territories. Some shreds of evidence in the literature suggest that dopaminergic neurons may be dysfunctional in CKD. Nevertheless, animal models' data are not clear and many observations suggest a minor relevance of the dopaminergic system in CKD-related cognitive impairment. However, a common sleep disturbance in CKD, the RLS, improves with dopaminergic drugs. CKD leads to cognitive and physical impairment, particularly in older adults. It remains to be established the role of the DA system in subtle motor dysfunction observed in CKD, such as tremors, gait alterations, and central sleep apnea.

Conflict of Interest Statement 

The authors have no conflicts of interest to declare. 

Funding Sources There was no funding for this study. 

Author Contributions P.M. and A.d.D. wrote and edited the manuscript; V.B. and G.B.: data collection and interpretation; P.M. and G.M.: study revision; P.M., A.d.D., and V.B.: study revision and editing. All authors read and approved the final manuscript.

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