<b><i>Background:</i></b> 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 (TNFE) is a cytokine endogenously expressed by the TAL and is also induced by AKI. Therefore, we hypothesized that TNFE is a key regulator of THP expression. <b><i>Methods:</i></b> We used a mouse model of AKI (ischemia-reperfusion injury, IRI) and a cell culture system of a TAL cell line (MKTAL). <b><i>Results:</i></b> We show that TNFE is upregulated by TAL cells early after AKI in vivo<i>. </i>The expression of THP and its transcription factor Hepatocyte nuclear factor 1F (HNF1F) were concomitantly decreased at the peak of injury. Furthermore, recombinant TNFE inhibits significantly, and in a dose-dependent manner, the expression of THP, but not HNF1F in MKTAL cells. Interestingly, neither TNFE neutralization nor genetic deletion of TNFE increased THP or HNF levels after injury in vivo. <b><i>Conclusion:</i></b> Our data suggest that TNFE can inhibit the expression of THP in TAL cells via an HNF1F-independent mechanism, but the downregulation of THP expression in the early AKI does not depend on TNFE. We propose that TNFE regulates THP expression in a homeostatic setting, but the impact of TNFE on THP during kidney injury is superseded by other factors that could inhibit HNF1F-mediated expression of THP. i 2014 S. Karger AG, Basel