Melamine Induces Human Renal Proximal Tubular Cell Injury via Transforming Growth Factor-β and Oxidative Stress

Abstract

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.

Ambient Melamine Exposure and Urinary Biomarkers of Early Renal Injury

“…8 This study found that melamine exposure was associated with NAG and b2-MG but not microalbumin, suggesting that the initial damage by melamine is mainly in renal tubular cells and is consistent with our previous in vitro study that showed that low and chronic melamine insult in human renal proximal tubular cells can increase cellular reactive oxygen species, decrease antiapoptotic/proapoptotic protein ratio, and eventually result in cell apoptosis prior to renal morphologic change. 26 Thus, the proposed mechanism in this study is quite different from that in the 2008 toxic milk scandal from China in which affected children suffered from acute renal injury directly caused by the formation of renal stones from the cocrystallization of melamine and other body ions, such as phosphate or uric acid, during urine filtration due to the large consumption of melamine-tainted baby milk formula.…”

Dual role of acetaminophen in promoting hepatoma cell apoptosis and kidney fibroblast proliferation

“…TGF-β-induced renal damage has been associated with: i) tubular cell death (68,70,71); ii) epithelial mesenchymal transition (72,73); and iii) fibroblast proliferation (74,75). Up to now, no study has provided evidence that APAP can induce kidney fibroblast proliferation via TGF-β-related signals.…”

Development of analytical method of melamine in placenta from pregnant women by isotope‐dilution liquid chromatography/tandem mass spectrometry

“…17 Placenta samples were analyzed using liquid-liquid extraction (LLE), SPE and isotope-dilution LC/MS/MS. 22,26 Briefly, placenta samples were added to 13…”

“…Several kinds of tableware are also made of melamine, which can migrate into food when that tableware comes into contact with high temperatures or acid . Several research groups studying long‐term low‐dose melamine exposure have suggested that melamine‐induced oxidative stress and inflammation play pathological roles in renal injury . Epidemiological studies have also associated melamine exposure and early renal injury markers in children and occupational workers …”

“…[8][9][10][11] Several research groups studying long-term low-dose melamine exposure have suggested that melamine-induced oxidative stress and inflammation play pathological roles in renal injury. [12][13][14][15][16] Epidemiological studies have also associated melamine exposure and early renal injury markers in children and occupational workers. 6,17,18 One review study has reported an increase in the number of animal studies suggesting that melamine may have physiological impacts beyond renal dysfunction, affecting reproductive function, neurology and anthropometric outcomes.…”