RT Journal Article
SR Electronic
T1 The kidney protects against sepsis by producing systemic uromodulin
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.08.425960
DO 10.1101/2021.01.08.425960
A1 Kaice A. LaFavers
A1 Chadi Hage
A1 Varun Gaur
A1 Radmila Micanovic
A1 Takashi Hato
A1 Shehnaz Khan
A1 Seth Winfree
A1 Simit Doshi
A1 Ranjani N. Moorthi
A1 Homer Twigg
A1 Xue-Ru Wu
A1 Pierre C. Dagher
A1 Edward Srour
A1 Tarek M. El-Achkar
YR 2022
UL http://biorxiv.org/content/early/2022/05/06/2021.01.08.425960.abstract
AB Sepsis is a significant cause of mortality in hospitalized patients. Concomitant development of acute kidney injury (AKI) increases sepsis mortality through unclear mechanisms. While electrolyte disturbances and toxic metabolite buildup during AKI could be important, it is possible that the kidney produces a protective molecule lost during sepsis with AKI. We previously demonstrated that systemic Tamm-Horsfall Protein (THP, uromodulin), a kidney-derived protein with immunomodulatory properties, falls in AKI. Using a mouse sepsis model without severe kidney injury, we show that the kidney increases circulating THP by enhancing basolateral release of THP from medullary thick ascending limb cells. In sepsis patients, changes in circulating THP are positively associated with critical illness. THP is also found de novo in injured lungs. Genetic ablation of THP in mice leads to increased mortality and bacterial burden during sepsis. Consistent with the increased bacterial burden, the presence of THP in vitro and in vivo leads macrophages and monocytes to upregulate a transcriptional program promoting cell migration, phagocytosis and chemotaxis and treatment of macrophages with purified THP increases phagocytosis. Rescue of septic THP-/- mice with exogenous systemic THP improves survival. Together, these findings suggest that through releasing THP, the kidney modulates the immune response in sepsis by enhancing mononuclear phagocyte function and systemic THP has therapeutic potential in sepsis.Significance Statement Sepsis is a significant contributor to kidney injury as well as morbidity and mortality worldwide. Specific therapies to improve outcomes in sepsis with kidney injury have largely been limited to symptom management and infectious agent control, in part because it is unclear how kidney injury increases sepsis mortality. This paper describes the identification of Tamm-Horsfall protein, previously known to protect in ischemic models of AKI, as protective in preclinical models of sepsis. It demonstrates how the loss of THP leads to decreased mononuclear phagocyte function and diversity, increased pathogen burden and decreased survival. THP also increases in sepsis without severe kidney injury and concentrates in injured organs. Further study of THP in sepsis could lead to novel sepsis therapeutics.Competing Interest StatementTEA and RM have applied for a patent related to this work titled Modified Tamm-Horsfall Protein and related compositions and methods of use, publication number US 2018/0305420 A1.