The Role of Tumor Necrosis Factor Alpha in Regulating the Expression of Tamm-Horsfall Protein (Uromodulin) in Thick Ascending Limbs during Kidney Injury

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BACKGROUND: Tamm-Horsfall Protein (THP) is a glycoprotein expressed exclusively by cells of the thick ascending loop (TAL) of Henle. THP has a protective role in acute kidney injury (AKI), and its expression is downregulated in the early stages of injury. Tumor necrosis factor alpha (TNFα) is a cytokine endogenously expressed by the TAL and is also induced by AKI. Therefore, we hypothesized that TNFα is a key regulator of THP expression. METHODS: We used a mouse model of AKI (ischemia-reperfusion injury, IRI) and a cell culture system of a TAL cell line (MKTAL). RESULTS: We show that TNFα is upregulated by TAL cells early after AKI in vivo. The expression of THP and its transcription factor Hepatocyte nuclear factor 1β (HNF1β) were concomitantly decreased at the peak of injury. Furthermore, recombinant TNFα inhibits significantly, and in a dose-dependent manner, the expression of THP, but not HNF1β in MKTAL cells. Interestingly, neither TNFα neutralization nor genetic deletion of TNFα increased THP or HNF levels after injury in vivo. CONCLUSION: Our data suggest that TNFα can inhibit the expression of THP in TAL cells via an HNF1β-independent mechanism, but the downregulation of THP expression in the early AKI does not depend on TNFα. We propose that TNFα regulates THP expression in a homeostatic setting, but the impact of TNFα on THP during kidney injury is superseded by other factors that could inhibit HNF1β-mediated expression of THP.

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