The kidney protects against sepsis by enhancing the systemic release of Uromodulin to stimulate macrophage function

Abstract

Sepsis is associated with significant mortality that persists despite advances in the care of critically ill patients. Concomitant development of acute kidney injury (AKI) markedly increases the mortality of sepsis through unclear mechanisms. While electrolyte disturbances and toxic metabolite buildup likely play a crucial role, loss of a protective molecule(s) from the injured kidney could also contribute to the dire outcomes observed in sepsis with AKI. Uromodulin (Tamm-Horsfall protein, THP) is a kidney-derived protein bidirectionally released in the urine and circulation. We previously showed that AKI causes acute systemic THP deficiency. Here, we show that circulating THP increases in experimental murine sepsis without severe AKI through basolateral shifting of its release within the kidney medulla. Concordantly, in asmall cohort of patient with sepsis and preserved kidney function, circulating THP positively correlates with the degree of critical illness, and accumulates in the lungs of a cohort of patients with ARDS. In a knockout mouse model with sepsis, we show that THP deficiency significantly increases mortality. Using single cell RNA-sequencing, we observe that THP expands a macrophage subset enriched with transcripts required for protein translation, migration and phagocytosis. Indeed, treatment of bone marrow-derived macrophages with THP enhances phagocytosis and the loss of THP in vivo causes an increases bacterial burden within organs during sepsis. Finally, treatment of septic THP^-/- mice with exogenous THP improves survival. Together, these findings suggest that THP protects from sepsis by enhancing macrophage function and its loss could explain the detrimental outcomes of sepsis with AKI. Our findings also suggest a potential therapeutic role of THP in sepsis.