The kidney protects against sepsis by producing systemic uromodulin

Area of Science:

• Nephrology
• Immunology
• Critical Care Medicine

Background:

• Sepsis is a leading cause of hospital mortality, with acute kidney injury (AKI) worsening outcomes via unknown mechanisms.
• The kidney-produced Tamm-Horsfall protein (THP), with known immunomodulatory roles, decreases in AKI.
• This study investigates THP's role in sepsis and its potential as a therapeutic agent.

Purpose of the Study:

• To determine if the kidney releases THP during sepsis to modulate the immune response.
• To investigate the protective effects of systemic THP in sepsis models.
• To explore THP's therapeutic potential in sepsis, particularly with co-occurring AKI.

Main Methods:

• Utilized a mouse sepsis model, examining THP levels and kidney release mechanisms.
• Analyzed circulating THP in human sepsis patients.
• Assessed the impact of THP deficiency and exogenous THP administration on sepsis outcomes and immune cell function in mice.
• Investigated THP's effect on macrophage and monocyte activity in vitro and in vivo.

Main Results:

• In a mouse sepsis model without severe AKI, the kidney increased circulating THP.
• Circulating THP levels correlated with illness severity in human sepsis patients.
• Genetic deletion of THP in mice increased sepsis mortality and bacterial load.
• THP enhanced the phagocytic and migratory functions of macrophages and monocytes.
• Systemic administration of THP improved survival in septic mice.

Conclusions:

• The kidney modulates the immune response in sepsis by releasing THP, which enhances mononuclear phagocyte function.
• Systemic THP demonstrates protective effects and holds therapeutic potential for sepsis, especially in the context of kidney injury.