The kidney is an immunologically active organ the size of a human fist (0.5% body weight). Yet 20?25 % of cardiac output traverses the kidney rendering it vulnerable to injury and loss of renal function. In renal diseases, complement (C) activation and macrophage (M) infiltration are two crucial events that occur. Both facets can be beneficial or detrimental, and behave differently at different locations depending on the microenvironment. Complement signaling directs M to sites of inflammation and participates in local M amplification, the numbers of which correlate negatively with renal function. Although M and C are intertwined, we are only beginning to understand how these two facets of inflammation interact. Gaining insight into the mechanisms at play in the regulation of trafficking and polarization of M by complement will open avenues for identification of novel therapeutics for kidney diseases that have no effective therapies. With the advent of advanced technology and better disease models, we are beginning to make inroads into better understanding glomerular, M and complement biology and the changes that occur during disease. The goal of the work proposed here is to understand glomerular inflammation using FH dependent immune complex mediated glomerulonephritis (ICGN) model. Our preliminary studies show that there is significant increase in recruitment of M and T lymphocytes across the glomerular filtration barrier, resulting in chronic inflammation that leads to fibrosis and functional renal failure in FH dependent ICGN. Based on our results, our hypothesis is that signaling through complement receptors leads to recruitment of M precursors to the kidney and alteration of M in the kidney, where they aggravate disease pathology. To test this hypothesis, we will (a) determine the role of M in FH dependent ICGN, (b) determine the impact of complement associated signaling on M in FH-dependent ICGN, and (c) determine the role of complement, Mo/M and glomerular/endothelial barrier (GEB) in FH-dependent ICGN. Our model of FH-dependent ICGN and GEB in culture are unique, with experimental features that are unrivaled. Thus, our studies using these models can provide considerable insights into mechanisms of disease relevant to human beings. We are well positioned to perform the proposed work, having all the necessary and innovative models (in vivo and in vitro) and validated technologies to interrogate these cells and pathways (e.g. molecular imaging, bone marrow transplants, genetic models and 18-color FACS analysis). We have also assembled a team of experts in macrophage biology, vascular biology, imaging and leukocyte trafficking, to accomplish our goals.
Complement system mediates the body?s defense system against infections, but excessive complement activation is linked to inflammatory diseases. The proposed project addresses innovative and important questions regarding the mechanism underlying complement activation, macrophages the defense cells, and inflammation. This study will lead to high impact findings with therapeutic implications for kidney disease, a condition that results in upto 70% reduction in life span.
