Melamine induces human renal proximal tubular cell injury via transforming growth factor-β and oxidative stress.
Although several reports have failed to observe adverse subchronic renal effects following relatively high melamine exposure, the safety of low and continuous melamine exposure is still debatable. Recent studies suggest that long-term, low-dose melamine exposure is associated with an increased risk of urolithiasis, which has been linked to chronic kidney disease (CKD). CKD is a consequence of nephron loss and is associated with the interaction of inflammation, oxidative stress, and transforming growth factor-β (TGF-β), which increases extracellular matrix genes and cell apoptosis with progression to fibrosis and end-stage renal disease. Thus far, information is still lacking regarding the influence of melamine at the gene and protein levels, which are activated at a much earlier phase than the occurrence of the renal morphological change. In this study, we stimulated human renal proximal tubular HK-2 cells with melamine (0, 125, 250, 500, or 1000 µg/ml) for different time intervals and observed its effects on several well-documented molecular mechanisms of CKD. Here, we demonstrate that melamine can activate mitogen-activated protein kinases, NFκB, and reactive oxygen species, which results in the upregulation of interleukin-6, monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, and TGF-β1 in HK-2 cells. The melamine-stimulated overexpression of TGF-β1 not only promotes fibronectin production but also leads to decreased antiapoptotic (bcl-2, bcl-xl)/proapoptotic (bad, bax) protein ratio, increased caspase-3 and caspase-9 activities, and eventually HK-2 cell apoptosis. Our study suggests that melamine exposure may be a risk factor for the chronic loss of tubular cells and may ultimately lead to tubulointerstitial damage.
Department of Medical Genetics, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan, R.O.C.
Tusty-Jiuan
TJ
Hsieh
Pei-Chen
PC
Hsieh
Yi-Hong
YH
Tsai
Chia-Fang
CF
Wu
Chia-Chu
CC
Liu
Ming-Yen
MY
Lin
Ming-Tsang
MT
Wu
D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005353:Fibronectins / Q000378:metabolism; D005506:Food Contamination; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics; D014227:Triazines / Q000633:toxicity*; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
D018932:Chemokine CCL2; D004785:Environmental Pollutants; D005353:Fibronectins; D015850:Interleukin-6; D053773:Transforming Growth Factor beta1; D014227:Triazines; D019010:Vascular Cell Adhesion Molecule-1; C011907:melamine