Meprin beta Modulates Expression of Inflammatory Mediators in IR-Induced Kidney Injury

Inflammation plays a central role in the progression of kidney injury induced by ischemia/reperfusion (IR). At the initiation of inflammation, circulating monocyte are recruited to the site of injury where they differentiate into either the classically activated M1 macrophages which produce several pro‐inflammatory cytokines, e.g., tumor necrosis factor α (TNF‐α), interleukins (e.g., IL‐6, IL‐10, and IL‐18), transforming growth factor β (TGF‐β), and chemokines (e.g., monocyte chemoattractant protein 1 (MCP‐1). This leads to recruitment of additional circulating monocytes to the site of injury, or the alternately activated M2 macrophages, which have anti‐inflammatory functions and are involved in tissue repair. Toll‐like receptors (TLRs), which are expressed by macrophages and dendritic cells, activate pro‐inflammatory cytokines (e.g., TNF‐α and IL‐1β). TLR2 and TLR4 activation leads to the nuclear translocation of NF‐κB, a key player in inflammation. Meprin metalloproteases are most abundantly expressed in the brush‐border membranes of proximal kidney tubules, which are the most susceptible to inflammation and IR‐induced kidney injury. Meprins were shown to enhance leukocyte infiltration through the extracellular matrix. Furthermore, meprins proteolytically process several pro‐inflammatory cytokines (e.g. IL‐1β, IL‐6, and IL‐18) and chemokines (e.g. MCP‐1). Meprin cleavage inactivates IL‐6, while cleavage of IL‐1β and pro IL‐18 activates them. However, the mechanisms by which meprins modulate inflammation are not fully understood. The current study used meprin β knockout (βKO) mice to better understand the role of meprins in the initiation and progression of IR‐induced kidney injury. We induced unilateral IR injury in wild‐type (WT) and βKO male mice. Kidneys were obtained at 24h and 48h post‐IR, and real‐time PCR used to determine the expression profiles of pro‐ and anti‐inflammatory modulators. The contralateral kidneys served as controls. Our data show that at 24h post‐IR, the levels of pro‐inflammatory mediator (TLR2) and anti‐ inflammatory cytokine (IL‐6) increased in WT but decreased in βKO kidneys. The levels of IL‐18 decreased in WT but did not change in βKO kidneys. In contrast, IL‐1β, TNF‐R1, NF‐κB increased in WT but did not change in βKO kidneys. The inflammatory mediators MCP‐1 and TLR‐4 and the anti‐inflammatory cytokine TNF‐R2 increased in kidneys subjected to IR in both genotypes. At 48h post‐IR, all the inflammation mediators shifted back toward the pre‐IR levels for WT mice. However, in βKO, the levels of TLR2 and TNFR2 continued to rise at 48h while IL‐18 levels significantly decreased. We previously demonstrated that meprin β expression enhances leukocyte infiltration in inflammation induced by unilateral ureteral obstruction (UUO). Data from the current study suggest that meprin β expressed in proximal tubules and leukocytes modulate synthesis of inflammatory mediators and could be responsible for exacerbating inflammation in the initiation phase of IR‐induced renal injury. Support or Funding Information NIH#SC1GM118271