Immune Mechanisms in Diabetic Nephropathy
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the US and in many developed countries around the world. Nonetheless, understanding of the pathogenesis of DN is limited and there is a significant unmet need for new, specific therapies to prevent or reverse kidney damage in DN. Our laboratory has developed a mouse model, combining type 1 diabetes with chronic, low-grade activation of the renin-angiotensin system (RAS), which recapitulates key features of human DN including. In microarray studies of glomerular mRNA, we have found that the development of DN is this mouse line is associated with broad up-regulation of gene expression patterns associated with immune activation and inflammation. Moreover, we find discordant mRNA signatures between mouse strains that are susceptible (S) or resistant (R) to DN, with activation of immune and inflammatory pathways in the S strain and broad suppression of these pathways in the R strain. Accordingly, we hypothesize that activation of the immune system is a key determinant of susceptibility to DN. RAS activation, which is critical for the development of DN in humans and in this mouse model, has powerful immunomodulatory effects. Therefore, we suggest that stimulation of adaptive and/or innate immune responses in DN is facilitated by angiotensin II acting via type 1 angiotensin (AT1) receptors in specific populations of immune and inflammatory cells. Although a role for inflammatory mechanisms in diabetic complications has been suggested previously, the specific contribution of inflammation to DN and the molecular triggers for immune activation in this setting are not clear. We will explore these issues using unique mouse lines developed in our laboratory through the following Specific Aims: 1. Define the role of T cell activation by angiotensin II in the development of DN; 2. Determine whether modulation of macrophage function by the RAS influences the pathogenesis of DN. We anticipate that these studies will provide new insights into the role of immune and inflammatory pathways in the pathogenesis of DN. Furthermore, they will define the capacity for cross-talk between the RAS and the immune system to modulate the severity of diabetic complications.

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