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<p>Chronic kidney disease (CKD) is a progressive disorder often aggravated by environmental exposure to waterborne metal pollutants, such as lead (Pb), cobalt (Co), copper (Cu), and zinc (Zn).These metals induce renal injury predominantly through oxidative stress and inflammatory pathways, with tumor necrosis factor-alpha (<i>TNF-α</i>) serving as a key mediator. The study aimed to investigate the association of the <i>TNF-α</i> -308 G/A (rs1800629) gene polymorphism and transmembrane(Tm)-<i>TNF-α</i> expression with the risk and severity of metal-induced CKD. A case–control study was conducted, including 80 patients with CKD (40 with early-stage and 40 with late-stage disease) and 40 age- and sex-matched healthy controls, selected according to stringent inclusion criteria. Metal concentrations were quantified using inductively coupled plasma mass spectrometry (ICP-MS), <i>TNF-α</i> genotyping was performed via amplification refractory mutation system-polymerase chain reaction (ARMS-PCR), and Tm-<i>TNF-α</i> levels were assessed by flow cytometry. The findings revealed that the A allele was significantly associated with increased CKD risk across dominant, recessive, and allelic genetic models. In a co-dominant model, the AA genotype conferred a fourfold and 15-fold higher risk for early- and late-stage CKD, respectively, compared to those with the GG genotype. Moreover, elevated Tm-<i>TNF-α</i> expression was significantly associated with the GA and AA genotypes and was most pronounced in late-stage CKD patients (p &lt; 0.001). These findings suggest that the <i>TNF-α</i> -308 G/A polymorphism markedly enhances susceptibility to metal-induced CKD, driven by increased Tm-<i>TNF-α</i> expression. Understanding this genetic variation elucidates the pathogenesis of metal-induced nephropathy and offers new opportunities for early diagnosis and targeted therapeutic development.</p> Graphical Abstract <p><b>The impact of Tumor necrosis factor-(</b><Emphasis Type="BoldItalic">TNF-α</Emphasis><b>)-alpha G/A polymorphism on the progress of metal-induced chronic kidney disease (CKD).</b> <i>TNF-α-</i>308 G/A variant is located in the promoter region and thus elevates the expression of <i>transmembrane (Tm)-TNF-α</i> protein, which is then cleaved by <i>TNF</i>-converting enzyme into its soluble(s)-<i>TNF-α</i> form. In metal-induced nephrotoxicity, elevated <i>TNF-α</i> production results in the deterioration of renal function and exacerbates the severity of chronic kidney disease (fibrosis).</p> <p></p>

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Association of Tumor Necrosis Factor Alpha Gene Polymorphism (TNF-α 308 G/A) with Enhanced Severity of Metal-Induced Chronic Kidney Disease via Upregulation of Transmembrane Protein Expression

  • 期刊论文

  • 发表日期：

    2025年5月13日

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  • Mohammed S. El-Gedamy,
  • Sherouk S. Elnagar,
  • El-Shaimaa E. Shabana,
  • Safaa A. Derbala

摘要

Chronic kidney disease (CKD) is a progressive disorder often aggravated by environmental exposure to waterborne metal pollutants, such as lead (Pb), cobalt (Co), copper (Cu), and zinc (Zn).These metals induce renal injury predominantly through oxidative stress and inflammatory pathways, with tumor necrosis factor-alpha (TNF-α) serving as a key mediator. The study aimed to investigate the association of the TNF-α -308 G/A (rs1800629) gene polymorphism and transmembrane(Tm)-TNF-α expression with the risk and severity of metal-induced CKD. A case–control study was conducted, including 80 patients with CKD (40 with early-stage and 40 with late-stage disease) and 40 age- and sex-matched healthy controls, selected according to stringent inclusion criteria. Metal concentrations were quantified using inductively coupled plasma mass spectrometry (ICP-MS), TNF-α genotyping was performed via amplification refractory mutation system-polymerase chain reaction (ARMS-PCR), and Tm-TNF-α levels were assessed by flow cytometry. The findings revealed that the A allele was significantly associated with increased CKD risk across dominant, recessive, and allelic genetic models. In a co-dominant model, the AA genotype conferred a fourfold and 15-fold higher risk for early- and late-stage CKD, respectively, compared to those with the GG genotype. Moreover, elevated Tm-TNF-α expression was significantly associated with the GA and AA genotypes and was most pronounced in late-stage CKD patients (p < 0.001). These findings suggest that the TNF-α -308 G/A polymorphism markedly enhances susceptibility to metal-induced CKD, driven by increased Tm-TNF-α expression. Understanding this genetic variation elucidates the pathogenesis of metal-induced nephropathy and offers new opportunities for early diagnosis and targeted therapeutic development.

Graphical Abstract

The impact of Tumor necrosis factor-(TNF-α)-alpha G/A polymorphism on the progress of metal-induced chronic kidney disease (CKD). TNF-α-308 G/A variant is located in the promoter region and thus elevates the expression of transmembrane (Tm)-TNF-α protein, which is then cleaved by TNF-converting enzyme into its soluble(s)-TNF-α form. In metal-induced nephrotoxicity, elevated TNF-α production results in the deterioration of renal function and exacerbates the severity of chronic kidney disease (fibrosis).