Targeting kidney resident macrophage niche filling to slow cystic kidney disease

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Project abstract Our data indicate that kidney resident macrophages (KRM) promote cystic kidney disease in multiple mouse models and that a similar population of KRM are present in humans suggesting that targeting these cells in patients with cystic kidney disease may have significant therapeutic benefits. However, it is not feasible to give patients KRM targeted inhibitors for long periods as these inhibitors deplete resident macrophages in multiple tissues, where their presence is required for basic biological functions including recycling red blood cells and fighting off infections. This problem is particularly relevant in the case of cystic kidney disease as patients experience periods of intermittent cyst growth over several decades. These data highlight the fact that a tissue specific approach to deplete KRM is desperately needed. In this application, we are proposing to study niche filling as a means to developing a tissue specific approach for long-term resident macrophage depletion. However, before we can accomplish this goal, we must first understand the mechanism of niche filling after temporary depletion, genes that are required for this process, and the influence of temporary depletion on long- term cyst growth. Based on our preliminary data, we hypothesize that Cx3cr1 is required for monocyte- dependent niche filling and cyst progression. This hypothesis will be tested using a monocyte-specific fate mapping mouse to track monocyte recruitment and engraftment into the KRM niche after depletion in both wild type and cystic mice. In subsequent aims, we will identify genes that are required for this process and test the idea that we can target a candidate gene, Cx3cr1, to delay KRM niche filling and slow cystic disease. Based on our exciting preliminary data, we propose that targeting Cx3cr1 may lead to a kidney specific approach for long- term resident macrophage depletion. This would have major impact on the cystic kidney disease field as well as any field in which KRM are involved in disease progression. This includes acute kidney injury and chronic kidney diseases, both of which are a major healthcare burden. 1