Vitamin D and calcium co-therapy mitigates pre-established cadmium nephropathy by regulating renal calcium homeostatic molecules and improving anti-oxidative and anti-inflammatory activities in rat

Cadmium (Cd) is a common environmental pollutant linked with multiorgan toxicity that could occur by ingestion, inhalation and/or cigarette smoking [1], [2]. Following chronic exposure, Cd2+ binds to albumin and other cysteine-containing peptides, including glutathione (GSH), and the heavy metal is then transported and deposited into several organs, with the kidney as the primary target for Cd2+ deposition [3], [4], [5]. Although filtered by the glomeruli, Cd2+ is reabsorbed in proximal tubular (PT) epithelial cells by endocytosis, thus accumulating in renal tissues, and subsequently inducing nephropathy [6], [7]. Cd2+ triggers renal cell damage by increasing the production of reactive oxygen species (ROS), deterring several antioxidant mechanisms, reducing cellular GSH, thus promoting oxidative stress, mitochondrial damage, and subsequently renal cell apoptosis/necrosis by increasing caspase-3 (Casp-3) expression [8], [9], [10]. Chronic Cd2+ toxicity also initiates cellular inflammatory responses by increasing tumor necrosis factor (TNF)-α, interleukin (IL)− 1β, IL-6, inducible nitric oxide synthase (iNOS), and transforming growth factor (TGF)-β alongside inhibiting the chief anti-inflammatory cytokine, IL-10 [11], [12], [13]. Furthermore, Cd2+ nephrotoxicity is associated with marked increases in neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), which are specific biomarkers of glomerular and tubular damage, respectively [14], [15].

Other pathomechanisms underlying Cd-induced cellular damage include disruption of cellular calcium (Ca2+) homeostasis, since the physicochemical characteristics of both divalent metals are almost identical [16], [17], [18]. Ca2+ is essential for cell biology, and the interchange between the extracellular ([Ca2+]E), cytosolic ([Ca2+]C) and intracellular ([Ca2+]I) Ca2+ is rigorously regulated [9], [17]. In more detail, [Ca2+]E moves into the cytosol via several membrane ionic channels, including the voltage-dependent Ca2+ channels (VDCCs) that are classified into transient (T; Cav3.1)- and long-lasting (L; Cav1.1)-types based on their voltage-gradient needs for activation [19], [20], [21]. At the intracellular level, [Ca2+]I is mainly stored in the endoplasmic reticulum (ER) and could be ejected into the cytosol via several store-operated channels (SOCs), including ryanodine (RyRs) and inositol triphosphate (ITPRs) receptors [22], [23]. Whilst Cd2+ pervades into the cytosol by activating Cav3.1, it can also block Ca2+ permeation by inhibiting Cav1.1 channel [19], [20], [21], as well as increasing [Ca2+]C by activating RyRs and ITPRs [22], [23], thus deregulating Ca2+-dependent cellular functions. Additionally, abnormal increases in [Ca2+]C stimulate calmodulin (CAM) and its dependent IIα protein kinase (CAMKIIα) eventually leading to mitochondrial damage, oxidative stress, and cell death [23], [24]. Similarly, the S100A1 and S100B cytosolic proteins are key Ca2+-signaling molecules, and the former is believed to be cytoprotective by blocking Ca2+ release from the ER, whilst the latter could trigger oxidative stress and inflammatory responses [25], [26].

Chelators have limited therapeutic value against chronic Cd2+ toxicity in clinical settings due to their associated adverse events, as well as their strong binding affinity with other vital divalent elements, such as iron and zinc [27], [28]. Therefore, a better approach would involve treatment with nutraceutical(s) that could inhibit Cd2+ absorption by enterocytes and/or deposition in targeted cells, alongside preventing oxidative stress, inflammation and the Ca2+ dyshomeostasis triggered by Cd2+ toxicity [9], [27]. Vitamin D (VD) is a steroid hormone that plays key roles in Ca2+-homeostasis, as well as exerting efficient anti-oxidative and anti-inflammatory actions [29], [30]. Circulatory VD (25-hydroxyvitamin D; 25-OH VD) is transported reversibly attached to its specific binding protein (VDBP), whereas active VD (VD3) is produced by renal tubular cells by the actions of the Cyp27b1 enzyme [31], [32]. VD3 triggers its cellular activities by stimulating its nuclear receptor (VDR), whilst its bioavailability is regulated by the Cyp24a1 catalyzing enzyme, and both are expressed in renal tissue [31], [32].

Several studies have documented significant decreases in serum 25-OH VD levels [33], [34], [35], inhibition of Cyp27b1 enzyme [33], [36], and downregulation of VDR [9], [37] with chronic Cd2+ toxicity. Moreover, marked increases in intestinal Cd2+ absorption together with accentuated toxicity were observed in animals fed with low amounts of VD or Ca2+ [38], [39], whilst their exogenous supplementations decreased Cd2+ intestinal uptake and promoted its excretion in urine [40], [41], [42]. We have also shown hepatoprotective effects against Cd2+-induced liver injury by prophylactic co-supplementation with VD and Ca2+ [9]. Hence, this study was conducted to measure the interactions between renal VD/Ca2+-homeostatic molecules with chronic Cd toxicity, as well as the potential therapeutic effects of VD3 and/or Ca2+ single and dual supplementations against Cd2+ nephrotoxicity that was established before treatment induction.

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