Tumor necrosis factor and interferon-gamma down-regulate Klotho in mice with colitis

Area of Science:

• Nephrology
• Immunology
• Gastroenterology

Background:

• Klotho (KL) is an anti-inflammatory protein crucial for endothelial health and calcium/phosphate homeostasis.
• KL deficiency is linked to premature aging and bone density issues, potentially contributing to inflammatory bowel disease (IBD)-associated osteopenia/osteoporosis.

Purpose of the Study:

• To investigate how colitis, a condition associated with IBD, affects renal Klotho expression.
• To explore the molecular mechanisms by which inflammatory cytokines influence Klotho expression in kidney cells.

Main Methods:

• Utilized three distinct mouse models of IBD-induced colitis.
• Examined the impact of tumor necrosis factor (TNF) and interferon-gamma (IFN-γ) on Klotho expression and promoter activity in renal epithelial cells.
• Assessed messenger RNA (mRNA) and protein levels of Klotho, as well as nitric oxide (NO) production.

Main Results:

• Renal Klotho mRNA and protein were significantly reduced in all three IBD models, correlating with colitis severity.
• Tumor necrosis factor (TNF) inhibited Klotho expression, an effect amplified by interferon-gamma (IFN-γ).
• These cytokines also increased inducible nitric oxide synthase (iNOS) and NO production, regulating Klotho transcriptionally.

Conclusions:

• The down-regulation of Klotho during inflammation may explain extraintestinal complications in IBD patients, such as bone homeostasis abnormalities.
• Targeting inflammatory pathways could potentially restore Klotho levels and mitigate IBD-related bone complications.