Mechanisms of cadmium nephrotoxicity
Chronic cadmium (Cd) exposure causes nephrotoxicity. The biochemical mechanism of Cd nephrotoxicity remains poorly understood. Upon Cd exposure, Cd is primarily deposited in liver, where it induces and binds to metallothionein (MT). The CdMT is released from hepatocyte and reabsorbed from glomerular filtrate by renal proximal tubular epithelial cells. The reabsorbed CdMT is rapidly degraded by the lysosomes releasing Cd++ into the cytoplasm, which binds to renal MT. The excess Cd++ results in oxidative stress. Antioxidants protect against Cd-induced nephrotoxicity. Morphologically, mitochondria are one of the earliest target organelles of Cd-induced nephrotoxicity. The renal mitochondrial dysfunction and the mechanism underlying Cd-induced apoptosis in the kidney remain to be elucidated and are the focus of this dissertation. ^ The present study demonstrates that CdMT administration causes mitochondrial dysfunction earlier than the marked effects on renal function and cytotoxicity. The mitochondrial effects in CdMT-injected rats include inhibition of electron transport, uncoupling of oxidative phosphorylation, and a decrease in respiratory control ratio. The similarity of the mitochondrial effects produced by CdMT administration in vivo and CdCl2 treatment in vitro suggests that Cd++ liberated from CdMT degradation is most probably responsible for the renal cortical mitochondrial dysfunction. ^ The relationship between Cd-induced mitochondrial dysfunction and apoptosis was examined in LLC-PK1 cells, a porcine kidney cell line. Cd treatment caused cell detachment and apoptosis in the detached cells. The Cd-induced apoptosis involved both mitochondrial membrane permeability transition and direct action of Cd on the nuclei. In the mitochondria Cd caused MPT pore opening that resulted in caspase-3 activation and DNA fragmentation. In nuclei, Cd treatment resulted in DNA fragmentation possibly by activation of endonucleases due to replacement of Ca. ^ Glycine protects against Cd nephrotoxicity in vivo by depressing oxidative stress. It appears that the primary sites of glycine protection is the liver. Whether glycine has a direct effect on Cd accumulation and cytotoxicity was examined in LLC-PK1 cells. The results indicate that glycine protects against acute cytotoxicity in these cells by interfering with Cd transport processes. This in vitro protective effect of glycine on acute Cd toxicity was not specific, as alanine was also protective. ^
Health Sciences, Toxicology|Health Sciences, Pharmacology
"Mechanisms of cadmium nephrotoxicity"
Dissertations and Master's Theses (Campus Access).