Kidney dysfunction and hypertension: role for cadmium, p450 and heme oxygenases?
Cadmium (Cd) is a metal toxin of continuing worldwide concern. Daily intake of Cd, albeit in small quantities, is associated with a number of adverse health effects which are attributable to distinct pathological changes in a variety of tissues and organs. In the present review, we focus on its renal tubular effects in people who have been exposed environmentally to Cd at levels below the provisional tolerable intake level set for the toxin. We highlight the data linking such low-level Cd intake with tubular injury, altered abundance of cytochromes P450 (CYPs) in the kidney and an expression of a hypertensive phenotype. We provide updated knowledge on renal and vascular effects of the eicosanoids 20-hydroxyeicosatetraenoic acid (20-HETE) and eicosatrienoic acids (EETs), which are biologically active metabolites from arachidonate metabolism mediated by certain CYPs in the kidney. We note the ability of Cd to elicit "oxidative stress" and to alter metal homeostasis notably of zinc which may lead to augmentation of the defense mechanisms involving induction of the antioxidant enzyme heme oxygenase-1 (HO-1) and the metal binding protein metallothionein (MT) in the kidney. We hypothesize that renal Cd accumulation triggers the host responses mediated by HO-1 and MT in an attempt to protect the kidney against injurious oxidative stress and to resist a rise in blood pressure levels. This hypothesis predicts that individuals with less active HO-1 (caused by the HO-1 genetic polymorphisms) are more likely to have renal injury and express a hypertensive phenotype following chronic ingestion of low-level Cd, compared with those having more active HO-1. Future analytical and molecular epidemiologic research should pave the way to the utility of induction of heme oxygenases together with dietary antioxidants in reducing the risk of kidney injury and hypertension in susceptible people.
National Research Center for Environmental Toxicology, University of Queensland, Brisbane, Australia. s.satarug@uq.edu.au
Soisungwan
S
Satarug
Muneko
M
Nishijo
Jerome M
JM
Lasker
Robert J
RJ
Edwards
Michael R
MR
Moore
D000818:Animals; D002104:Cadmium / Q000378:metabolism* / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006977:Hypertension, Renal / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
D002104:Cadmium; D003577:Cytochrome P-450 Enzyme System; D006419:Heme Oxygenase (Decyclizing)