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

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 (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. 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 TNFE is upregulated by TAL cells early after AKI in vivo. 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. Conclusion: 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that TNFE regulates THP expression in a homeostatic setting, but the impact of TNFE on THP during kidney injury is superseded by other factors that could inhibit HNF1F-mediated expression of THP.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