Chronic kidney diseases (CKD) are among the most significant public health problems with an aggregate prevalence of ~15% and virtually no curative therapies. The most promising group of disorders that may allow identification of urgently needed CKD drug targets are those with a known underlying molecular defect. Among them, the most prevalent and most commonly leading to end-stage renal disease (ESRD) is autosomal dominant polycystic kidney disease (ADPKD; 600,000 patients in the US; the fourth leading cause of ESRD). Because the diagnosis cannot be excluded until age 40, many ADPKD patients are veterans. While mechanisms that trigger or promote the pathogenesis of ADPKD are not yet completely understood, we and others have pointed to specific renal immune cells as key outcome regulators of renal cystic disorders in mice. Our preliminary data show that these renal immune cells include T-cells, a common renal immune cell type, and recently defined sub- populations of renal mononuclear phagocytes/macrophages (MP) that control the activity of specific T-cell sub- lineages. These T-cells, in turn, secrete factors that promote recruitment/differentiation of MPs. As our additional preliminary data suggest, this positive feedback loop can be triggered or enhanced by specific intra-cystic microbiota that promote the activity of specific T-cell sub-lineages. Disruption of this feedback loop at the level of MPs or lymphocytic lineage attenuates renal cystogenesis in mouse models. Therefore, this pathway represents an attractive therapeutic target. However, several critical gaps in knowledge must be addressed first, e.g., to establish a causal relationship between microbiota, abnormal T-cell responses in cystic kidneys and relevance of this concept to human ADPKD patients. The objective of the proposed studies is to address these limitations by interventional studies in a mouse model and by validating this concept in ADPKD patients. Together our preliminary studies support a model in which distinct evolutionarily-conserved inter-cellular signaling networks regulate intra-renal T-cell functional diversification that, in turn, controls epithelial differentiation abnormalities that enhance ADPKD progression. We will test the relevance of this model to ADPKD patients in three inter-related aims: i) Test the hypothesis that reduction of microbiota-stimulating effects on Th17 cells attenuates renal cystogenesis in mice; ii) Test the hypothesis that enhancement of Th17 activity by specific bacterial species exacerbates renal cystogenesis in mice; iii) Test the hypothesis that plasma or urinary markers of abnormal Th17 activity correlate with rate of renal cyst growth and predict renal function loss in ADPKD patients. Accomplishing the goals of this project will allow us to apply the wealth of genetic and cellular information obtained from the functional counterparts in mouse studies to human patients, provide a means for a more accurate assessment of ADPKD severity, and open new avenues to improve ADPKD outcomes.

Public Health Relevance

Both innate and adaptive immunity have been a major focus of research for decades, yet most studies fail to appreciate their important functional complexities and tissue-specific heterogeneity, especially in the context of humans with renal disorders. The objective of this Project is to provide one of the first steps towards comprehensive evaluation of adaptive immune response heterogeneity induced by microbiota in a model of renal cystic disease, and to demonstrate its relevance to autosomal dominant polycystic kidney disease (ADPKD), one of the most common genetically-defined disorders. Building on strong preliminary data from mouse models, and thanks to our ready access to fresh and archived human samples that are linked with clinical information/outcomes, we will define key characteristics of microbiota-induced adaptive immune responses, and determine their fate in pathogenesis and prediction of ADPKD outcomes.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Emphasis Panel (ZRD1)
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Birmingham VA Medical Center
United States
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