**9. Postulated Model of Cadmium-Induced Proximal Tubule Lesion**

Prozialeck and Edwards proposed a model of proximal convoluted tubular cell injury in 2012 [50] that we think elaborates very well the mechanism of cadmium-induced kidney injury in terms of oxidative damage as a unifying mechanism. This model is similar to what has been proposed to explain the mechanisms of ischemic acute kidney injury [8,10,200,201]. Essentially, as diagramed in Figure 6, under healthy conditions and in the absence of cadmium deposit and accumulation, epithelial cells in the proximal tubule are closely associated with each other via specialized junctional structures. These epithelial cells align orderly and tightly on the tubular basement membrane via local adhesion molecules to collectively achieve filtration and reabsorption. In the presence of cadmium, which can accumulate in the cytosolic and mitochondrial compartments, cadmium binds thiol-containing proteins and peptides, leading to functional impairment of these cadmium-bound proteins and peptides. Consequently, such impairments cause mitochondrial electron leakage or NADPH oxidase dysfunction, resulting in enhanced production of ROS and elevated levels of oxidative stress. If the oxidative stress is mild, the tubular cells can repair themselves and resume normal function. It should be noted that this self-repair is likely achieved by de-differentiated tubular epithelial cells instead of differentiated and fixed tubular progenitor cells [202,203]. However, if the oxidative stress is severe and overwhelms cellular repair capacity, an irreversible damage process occurs and cells die by means of apoptosis, necrosis or both [204,205], leading to cell-cell and cell-basement membrane dissociations. This would lead to proteinuria, polyuria, and a progressive decline in kidney function. This functional decline, however, may be intervened and halted by the antioxidative approaches shown in Table 1 if applied appropriately. It should be pointed out that in order to distinguish cadmium-induced proteinuria from primary glomerular lesion, the magnitude of proteinuria and a cadmium concentration dependent manner will need to be characterized.

**Figure 6.** Schematic diagram depicting cadmium-induced injury to proximal tubular epithelial cells. When oxidative damage is mild, the cells can mobilize their repair defense system and self-repair, leading to maintenance of cellular function. When oxidative damage is severe, cells lose their self-repair capacity and die, leading to widespread cell death and kidney injury. (Adapted from reference [50]).
