Remote injury responses after AKI

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PROJECT SUMMARY ABSTRACT The overall goal of our research is to develop novel strategies to treat secondary complications of acute kidney injury (AKI). Remote acute lung injury (ALI) is a frequent and often lethal complication of acute kidney injury (AKI) that lacks therapies. Molecular mechanisms of AKI-ALI are incompletely understood, but circulating inflammatory cytokines, e.g. tumor-necrosis-factor (TNF) and T cells have been implicated. Which specific kidney cell types release and which lung cell types or immune cells are targeted by these mediators is unknown. Macrophage accumulation in the lung has been reported in AKI-ALI in mice and human, but whether this occurs by recruitment of bone marrow-derived circulating CCR2+monocytes or proliferation of tissue resident macrophages is unknown. Macrophage responses as well as their heterogeneity are critical determinants of tissue responses to injury. The overall lung remote immune response to AKI and the origin and heterogeneity of lung macrophages in AKI-ALI are unknown. The objective of this application is to determine the role of proximal tubule cell (PTC)- derived TNF and of TNFR1 in lung interstitial macrophages in AKI-ALI, to determine the origin and heterogeneity of kidney/lung macrophages after AKI, and to compare local and remote injury responses in kidney and lung after AKI. Our central hypothesis is (1) PTC-derived TNF is an AKI-ALI mediators and (2) local and remote immune responses share common features but have important differences. Our preliminary work suggests that PTC-derived TNF mediates inflammation and CCR2+-dependent interstitial macrophage recruitment to the lung, and targets lung interstitial macrophages. We detect similarities in local and remote injury responses, but also significant differences, e.g in response of the lung to AKI vs. to acute myocardial infarction. The rationale for this project is that completion will (1) identify PTC-derived TNF as an AKI-ALI mediators, and lung interstitial macrophages as its target cell in the lung, and (2) identify common features and significant differences in local and remote immune responses that could be exploited for targeted therapies. We plan to test our central hypothesis with two specific aims: AIM 1: Determine the role of PTC-derived TNF and of TNFR1 interstitial macrophage knockout in AKI-ALI (using cell type-specific KO mice) AIM 2: Determine the origin of interstitial macrophages in AKI-ALI and their heterogeneity, and compare local kidney immune cell responses to remote lung immune cell responses in AKI-ALI (using fate-mapping and scRNAseq). As outcomes, we expect that TNF- PTC-KO protects against AKI-ALI, and that comparison of local and remote injury responses identifies important differences. This contribution is significant because it is expected to have translational impact in the development of treatments for secondary AKI complications with high mortality, such as AKI-ALI. Our research is innovative, in our opinion, because, it would for the first time identify the source (PTC) and target cells (interstitial macrophages_ of AKI-ALI mediators in the kidney, and for the first time use single cell RNAseq to define local and remote immune responses AKI-ALI.