Vascular system function involves complex interactions among the vascular endothelium, smooth muscle, the immune system, and the nervous system. The toxic metals cadmium (Cd), arsenic (As), and lead (Pb) can target the vascular system in a variety of ways, ranging from hemorrhagic injury to subtle pathogenic remodeling and metabolic changes. Acute Cd exposure results in hemorrhagic injury to the testis, although some strains of animals are resistant to this effect. A comparison of Cd-sensitive with Cd-resistant mouse strains showed that expression of the Slc39a8 gene, encoding the ZIP8 transporter, in the testis vasculature endothelium is responsible for this difference. Endogenously, ZIP8 is a Mn²⁺/HCO₃^–symporter that may also contribute to Cd damage in the kidney. Chronic Cd exposure is associated with various cardiovascular disorders such as hypertension and cardiomyopathy and it is reported to have both carcinogenic and anticarcinogenic activities. At noncytotoxic concentrations of 10–100nM, Cd can inhibit chemotaxis and tube formation of vascular endothelial cells. These angiostatic effects may be mediated through disruption of vascular endothelial cadherin, a Ca²⁺-dependent cell adhesion molecule. With regard to As, ingestion of water containing disease-promoting concentrations of As promotes capillarization of the liver sinusoidal endothelium. Because capillarization is a hallmark precursor for liver fibrosis and contributes to an imbalance of lipid metabolism, this As effect on hepatic endothelial cells may be a pathogenic mechanism underlying As-related vascular diseases. With regard to Pb, perinatal exposure may cause sustained elevations in adult blood pressure, and genetically susceptible animals may show enhanced sensitivity to this effect. Taken together, these data indicate that the vascular system is a critical target of metal toxicity and that actions of metals on the vascular system may play important roles in mediating the pathophysiologic effects of metals in specific target organs.

Cadmium is an important industrial agent and environmental pollutant that is a major cause of kidney disease. With chronic exposure, cadmium accumulates in the epithelial cells of the proximal tubule, resulting in a generalized reabsorptive dysfunction characterized by polyuria and low-molecular-weight proteinuria. The traditional view has been that as cadmium accumulates in proximal tubule cells, it produces a variety of relatively nonspecific toxic effects that result in the death of renal epithelial cells through necrotic or apoptotic mechanisms. However, a growing volume of evidence suggests that rather than merely being a consequence of cell death, the early stages of cadmium-induced proximal tubule injury may involve much more specific changes in cell-cell adhesion, cellular signaling pathways, and autophagic responses that occur well before the onset of necrosis or apoptosis. In this commentary, we summarize these recent findings, and we offer our own perspectives as to how they relate to the toxic actions of cadmium in the kidney. In addition, we highlight recent findings, suggesting that it may be possible to detect the early stages of cadmium toxicity through the use of improved biomarkers. Finally, some of the therapeutic implications of these findings will be considered. Because cadmium is, in many respects, a model cumulative nephrotoxicant, these insights may have broader implications regarding the general mechanisms through which a variety of drugs and toxic chemicals damage the kidney.

Cadmium (Cd) exposure results in injury to the proximal tubule characterized by polyuria and proteinuria. Kidney injury molecule-1 (Kim-1) is a transmembrane glycoprotein not normally detected in the mature kidney, but is upregulated and shed into the urine following nephrotoxic injury. In this study, we determine if Kim-1 might be a useful early biomarker of Cd nephrotoxicity. Male Sprague–Dawley rats were given daily injections of Cd for up to 12 weeks. Weekly urine samples were analyzed for Kim-1, protein, creatinine, metallothionein, and Clara cell protein CC-16. Significant levels of Kim-1 were detected in the urine by 6 weeks and continued to increase throughout the treatment period. This appearance of Kim-1 occurred 4–5 weeks before the onset of proteinuria, and 1–3 weeks before the appearance of metallothionein and CC-16. Higher doses of Cd gave rise to higher Kim-1 excretion. Reverse transcriptase-polymerase chain reaction (RT-PCR) expression analysis showed that Kim-1 transcript levels were increased after 6 weeks at the low dose of Cd. Immunohistochemical analysis showed that Kim-1 was present in proximal tubule cells of the Cd-treated rats. Our results suggest that Kim-1 may be a useful biomarker of early stages of Cd-induced proximal tubule injury.

The classical cadherins such as E- and N-cadherin are Ca²⁺-dependent cell adhesion molecules that play important roles in the development and maintenance of renal epithelial polarity. Recent studies have shown that a variety of cadherins are present in the kidney and are differentially expressed in various segments of the nephron. However, the interpretation of these findings has been complicated by the fact that the various studies focused on different panels of cadherins and utilized different species. Moreover, since only a few of the previous studies focused on the rat, information regarding the expression and localization of renal cadherins in this important species is lacking. In the present study, we have employed dual immunofluorescent labeling procedures that utilized specific antibodies against either E- or N-cadherin, along with antibodies that target markers for specific nephron segments, to characterize the patterns of cadherin expression in frozen sections of adult rat kidney. The results showed that N-cadherin is the predominant cadherin in the proximal tubule, but is essentially absent in other nephron segments. By contrast, E-cadherin is abundant in the distal tubule, collecting duct and most medullary segments, but is present only at very low levels in the proximal tubule. Additional results revealed different patterns of N-cadherin labeling along various segments of the proximal tubule. The S1 and S2 segments exhibit a fine threadlike pattern of labeling at the apical cell surface, whereas the S3 segment show intense labeling at the lateral cell-cell contacts. These results indicate that E- and N-cadherin are differentially expressed in the proximal and distal tubules of rat kidney and they raise the possibility that differences in cadherin expression and localization may contribute to the differences in the susceptibility of various nephron segments to renal pathology or nephrotoxic injury.