**1. Introduction**

The kidney is a vital organ that performs critical physiological functions by actively filtering excess fluid and secreting waste products including urea, uric acid, and creatinine [1,2]. It is through the process of filtration and reabsorption that the kidneys maintain homeostasis of water, acid-base and, electrolytes [3]. Moreover, the kidney also secretes hormones that participate in the control and regulation of hemodynamics, red blood cell production, and vitamin D maturation [3]. Under abnormal conditions such as fasting and insulin resistance, the kidney can also make glucose via the gluconeogenic pathway [4–6] using noncarbohydrate precursors such as pyruvate, alanine, lactate, and glycerol [7].

The kidney is also vulnerable to injuries caused by numerous challenges such as ischemia [8–12], drug toxicity [13–19], environmental heavy metal exposure [20–27], hypertension [28–30], immune injury [31,32], and diabetes [33–36]. In terms of environmental risk factors, human kidney disease caused by environmental pollutants and occupational-linked toxins is a major public health issue [37]. Cadmium is a toxic heavy metal mainly derived from chemical stabilizers, pigments, nickel-cadmium batteries, and metal coatings and alloys [38]. It is also a toxic element in cigarettes [38]. Accordingly, contaminated soil, air, drinking water, food chains [39,40], and cigarettes, as well as children's plastic toys [41], are the major sources of human cadmium exposure. Numerous studies focusing on cadmium toxicity have established that the kidney is a primary organ site for cadmium accumulation [42,43]. Indeed, cadmium exposure has been tightly associated with renal dysfunction and kidney damage, causing polyuria and proteinuria [23,24]. The proximal tubule is the major site of cadmium deposition, accumulation, and damage because of the development of proximal tubular

**Citation:** Yan, L.-J.; Allen, D.C. Cadmium-Induced Kidney Injury: Oxidative Damage as a Unifying Mechanism. *Biomolecules* **2021**, *11*, 1575. https://doi.org/10.3390/ biom11111575

Academic Editor: Theodoros Eleftheriadis

Received: 16 September 2021 Accepted: 20 October 2021 Published: 23 October 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

epithelial cell hypertrophy with occurrence of polyuria and proteinuria [44–46]. Therefore, it is important to counteract cadmium-induced kidney injury to safeguard kidney function.

#### **2. Cadmium Absorption, Transportation, and Accumulation in the Kidney**

Cadmium has a high affinity toward thiol groups and can selectively form complexes with proteins and peptides whose cysteine residues are available for cadmium binding [47,48]. After ingestion of cadmium-contaminated water, food, and/or cigarette smoking, cadmium can be absorbed into circulation via the gastrointestinal tract, respiratory tract, or the skin [49–51]. Once in the blood, cadmium binds to albumin and other cysteine-containing proteins and peptides such as glutathione [37] and gets transported via many avenues to the liver [37] whereby the heavy metal is then released and induces the expression of metallothionein that then binds tightly to cadmium [52,53]. This binding serves the purpose of detoxification as the cadmium-metallothionein complex is usually considered nontoxic [54]. The cadmiummetallothionein complex can be released into the bloodstream and is then filtered at the glomerulus and reabsorbed by the proximal tubular epithelial cells [55]. This is followed by release of cadmium from the degradation of the cadmium-metallothionein complex [55]. The free form of cadmium in the proximal tubular region of the nephron can then bind to preexisting renal metallothionein and induce further renal expression of metallothionein [50]. When renal metallothionein is exhausted [56,57], the nonmetallothionein bound cadmium accumulates and induces nephrotoxicity [49–51,58,59], primarily in the proximal tubular region (Figure 1) via generation of oxygen free radicals [60–62]. As up to 50% of the body's cadmium pool can deposit in the kidney [37] and the half-life of cadmium in the kidney is approximately 45 years [63–67], cadmium-caused renal toxicity can pose a major threat to human health, particularly in countries where environmental control and regulation are lacking. It should be noted that while the binding of cadmium to metallothionein is a well-established mechanism, other thiol-containing proteins and peptides such as albumin and glutathione can also bind cadmium, leading to functional impairment of these cadmium bound target proteins and peptides [50].

**Figure 1.** Diagram showing the proximal convoluted tubule as the major site of cadmium accumulation and toxicity in the nephrons "\*".

#### **3. Cadmium-Induced Animal Models of Kidney Injury**

Given the fact that human cadmium exposure is a chronic process at a very low level, any investigation of cadmium renal toxicity would require many years of monitoring and follow-up studies. Therefore, animal models using mice or rats have been widely used to replicate the pathophysiological mechanisms of cadmium renal toxicity [39,40,42,68]. In numerous cases, high doses of cadmium were applied in these animal models to shorten the

duration of the studies and facilitate the process of obtaining insights into the mechanisms of cadmium renal toxicity. As mentioned above, studies using rodent models as well as results from human subjects have established that the primary target of cadmium in the nephron is the proximal tubule, whereby cadmium causes overall dysfunction of the epithelial cells [51,69,70], resulting in polyuria and proteinuria [50,51]. There is also an increase in urinary excretion of amino acids, glucose, and electrolytes such as Na+. K+, and Ca2+ [50,51]. Increasing evidence also indicates that a variety of risk factors such as aging [71], malnutrition [72], obesity [73–75], and diabetes [27,76] can further superimpose on cadmium renal toxicity and aggravate cadmium-induced renal dysfunction.

It should be stressed that in animal model studies of cadmium renal injury, a variety of doses, routes, and duration of exposures have been performed. The purpose of all these approaches is to try to replicate or recapitulate the toxico-kinetics and underlying mechanisms of long-term, low-level exposure that commonly occur in humans [50].

#### **4. Mechanisms of Cadmium-Induced Renal Toxicity**

What is the proposed mechanism of cadmium-induced kidney injury? Based on numerous studies, all injurious pathways converge on ROS production and culminate in oxidative stress [77–81], which suggests that oxidative damage is a unifying mechanism of cadmiuminduced renal toxicity and injury. We also think that the major sources of ROS causing oxidative damage in this context are mitochondria and NADPH oxidase, described as follows.

#### **5. Sources of Reactive Oxygen Species**

#### *5.1. Mitochondria*

Mitochondria are well known as the intracellular site of ROS production [82–85]. Among the electron transport chain components complexes I, II and III have all been established as major sites of ROS production [86–89]. These sites are not perfect even under normal conditions and can leak electrons out of the transport chain [90,91] (Figure 2). The leaked electrons can then partially reduce oxygen to form superoxide anion, which is the precursor of all other reactive oxygen species including H2O2, hydroxyl radical, and peroxynitrite [92,93] (Figure 3). Additionally, dihydrolipoamide dehydrogenase involved enzyme complexes such as pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and branched chain amino acid dehydrogenase can also produce superoxide anion in a variety of experimental and pathological conditions [94–97].

**Figure 2.** Diagram showing mitochondrial electron transport chain and oxidative phosphorylation. Complexes I, II, and III all can generate superoxide anion. This process can be enhanced by pathophysiological conditions such as cadmium exposure and accumulation. Note that it has been suggested that complexes II and III are the likely sites interacting with cadmium [98].

**Figure 3.** Production of other reactive oxygen species and reactive nitrogen species from the initial species superoxide. Superoxide can be dismutated by superoxide dismutase to form H2O2, which can be further detoxified by catalase. In the presence of metal ions such as iron, H2O2 can also generate very reactive species hydroxyl radical. Additionally, superoxide can react with nitric oxide to form peroxynitrite that is also very reactive toward macromolecules.
