Macrophage Function in Kidney Repair

描述（由申请人提供）：急性肾损伤（AKI）是住院患者的常见病。损伤导致局部和全身反应，以清除受损的小管细胞，并刺激存活的细胞重建正常的小管结构。研究

DESCRIPTION (provided by applicant): Acute Kidney Injury (AKI) is a common occurrence in hospitalized patients. The injury leads to both local and systemic responses to remove damaged tubular cells and stimulate surviving cells to reconstitute the normal tubule architecture. Studies using multiple rodent models of kidney injury have shown that macrophages progressively accumulate in the kidney after injury and undergo a transition from a proinflammatory (M1-like) phenotype to an alternatively activated (M2-like) phenotype that is required for normal repair to occur. However, the signals that regulate that M1 to M2 transition in vivo, as well as the actual M2-derived factors that are promoting normal repair, are as yet unknown. Our data demonstrate that the switch from proinflammatory expression to alternative activation can occur via activation of 2 distinct signaling pathways (Stat3 and Stat6) in coordination with secondary signaling by the proinflammatory TLR-dependent M1 activation pathway (MyD88/NFkB) and the inflammasome. Furthermore, we have found that tubular cells secrete/shed endogenous TLR ligands along with the gp130/Stat3 activator Lif to activate these signaling events. Analysis of macrophages isolated from injured kidneys at the time of M1-M2 transition reveals >100-fold increase in expression of two proteins, Arg1 and Brp39, both of which are strongly implicated in promoting tubular cell survival and proliferation. The studies described in this proposal are designed to identify the in vitro signaling events that regulate Arg1 and Brp39 expression during M1-M2 transition (Aim1), to define the in vivo importance of those pathways for the expression of these reparative factors and for suppressing tubule injury and promoting repair in murine and human AKI (Aim 2), and to perform selective in vitro and in vivo macrophage priming as a therapeutic approach to promote repair after acute kidney injury. PUBLIC HEALTH RELEVANCE: The kidneys can be injured and stop functioning, yet they have the ability to replace the damaged cells with new ones and thus restore function. We have identified macrophages as a prominent regulator of this repair process. Our current proposal is focused on learning how macrophages promote kidney repair and developing approaches to use them for therapy.