Mechanisms of Cadmium-Induced Proximal Tubule Injury: New Insights with Implications for Biomonitoring and Therapeutic Interventions

Abstract

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.

Kidney Cadmium Toxicity, Diabetes and High Blood Pressure: The Perfect Storm

“…Following acute Cd exposure the liver is the prime site of toxicity. However, with chronic exposure, high levels of Cd do not remain in the liver but redistribute to the kidney, where it accumulates in tubular epithelial cells (Prozialeck and Edwards 2012). Cd that enters the systemic blood circulation can either be loosely associated with albumin, amino acids, glutathione or tightly bound to MT.…”

Cadmium affects osmotic phase and regulatory volume decrease in cultured human embryonic kidney cells

“…13,30 Being renal cells continuously exposed to physiological changes in the osmolarity of the external medium, 31 cell lines derived from kidney are a suitable model for monitoring homeostatic cell functions, such as the regulation of cellular volume, in the presence of xenobiotics. 32,33 Our results show that HEK 293 cells exhibit the expected OP within 4 min of 15% hyposmotic challenge, leading to water influx, as shown in other cell types. 18 After OP, RVD phase occurs and is completed within 30 min of hyposmotic shock application, with cell volume recovering, due to both K + and Cl -outflow, resulting in water efflux.…”

Amelioration of Hepato-Renal Toxicity by a Flavonoid-Rich Fraction of Hibiscus rosa-sinenses (Leaves and Flowers) in Male Rabbits Intoxicated by Cadmium

“…It also creates a great number of non-specific toxicological issues resulting in a decease of renal cells via apoptosis or necrosis. However, it is also proposed that early stages of Cd-induced proximal tubular destruction may implicate much more specific alterations in cell-cell adhesions, autophagy responses, and signaling pathways in cells, which happen well before the inception of necrotic or apoptotic damage [42]. Renal tissues are more vulnerable to damage because of greater perfusion and a large number of combinations are excreted by renal tubular cells.…”