Kidney Dysfunction and Hypertension: Role for Cadmium, P450 and Heme Oxygenases?

Invited Review

Kidney Dysfunction and Hypertension: Role for
Cadmium, P450 and Heme Oxygenases?

SOISUNGWAN SATARUG,^{1,
2} MUNEKO NISHIJO,³ JEROME M. LASKER,⁴
ROBERT J. EDWARDS⁵ and MICHAEL R. MOORE¹

¹National Research Center for Environmental Toxicology (EnTOX), the University of Queensland, Brisbane, QLD, Australia,
²Biomedical Sciences Program, Thammasat University, Rungsit Campus, Pathumthani, Thailand,
³Department of Public Health, Kanazawa University Medical School, Ishikawa, Japan,
⁴Institute for Biomedical Research, Hackensack University Medical Center, Hackensack, NJ, USA, and
⁵Experimental Medicine and Toxicology, Imperial College London, Hammersmith Campus, London, UK

1. The kidney as a critical target in non-occupationally exposed populations   183
      1.1 Sources and the half-life of Cd deposited in the human kidney
      1.2 Renal Cd toxicities and adverse health outcomes
      1.3 Molecular mechanisms underlying renal Cd toxicity
2. Cd nephropathy and hypertension: Are they linked?   185
      2.1 Experimental induction of hypertension with low-dose Cd
      2.2 High blood pressure arising in men with signs of Cd-linked tubular injury and dysfunction
      2.3 Putative pathophysiologic mechanisms linking Cd nephropathy with expression of a hypertensive phenotype
3. The kidney as regulator of long-term blood pressure levels   188
      3.1 Cytochromes P450 (CYPs) superfamily and their quantification
      3.2 Emerging role for the eicosanoids derived from CYP-mediated lipid metabolism in the control of tubular function and systemic blood pressure
      3.3 Renal and vascular effects of eicosanoids
      3.4 Expression of CYPs in the human kidney in relation to Cd content, urinary 20-HETE excretion and a hypertensive phenotype
      3.5 Emerging role for heme oxygenase as a renal protector and a depressor
      3.6 Inductionof the renal HO-1 gene expression by Cd
4. A hypothetical model showing Cd molecular targets and defense mechanisms in proximal tubular cells in response to Cd load   195
Conluding Remarks   196

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 “xidative 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.

keywords —— cadmium; kidney; cytochromes P450; heme oxygenases; 20-hydroxyeicosatetraenoic acid

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Tohoku J. Exp. Med., 2006, 208, 179-202

Received January 13, 2006; revision accepted for publication January 17, 2006. Correspondence:
Dr. Soisungwan Satarug, National Research Center for Environmental Toxicology (EnTOX), The University of Queensland, 39 Kessels Road, Coopers Plains, Brisbane, Queensland 4108, Australia.

e-mail:s.satarug@uq.edu.au