Lupus nephritis is believed to result from glomerular deposition of immune complexes, triggering local kidney inflammation, followed by worsening glomerulosclerosis and end stage renal disease. The mechanisms responsible for this chronic kidney disease progression are poorly understood. Several reports and our preliminary data suggest a link between decreases in T cell production of transforming growth factor beta (TGFbeta) with autoantibody production, and increases in renal TGFbeta expression with the development of chronic kidney lesions. The central hypothesis of this proposal is that TGFbeta plays dual roles in the development and progression of lupus nephritis: while decreased TGFbeta levels promote early stage lupus nephritis by enhancing T and B cell activation and autoantibody production, increased TGFbeta levels accelerate late stage kidney disease by inducing increased extracellular matrix production. The proposed studies will evaluate changes in the expression levels of TGFb, its receptors and signaling proteins in the lymphoid and renal tissues during progression of kidney disease in murine models of lupus. These studies will build on preliminary data indicating that urine TGFbeta levels rise in response to increases in TGFbeta activity in lupus kidney cells, thus serving as a diagnostic marker for chronic kidney damage. The proposed studies will also investigate the potential mechanisms of renal TGFb overexpression in lupus, and more importantly, determine the contribution of the TGFbeta system to autoantibody production and kidney damage. TGFbeta blockade in vivo using monoclonal antibodies will be investigated as a potential therapeutic approach that could inhibit or reverse the development of chronic kidney lupus disease, without worsening autoimmunity. Our broad goals in this proposal are to understand the mechanisms of kidney damage in lupus. Relevant to the current RFA, this proposal will: a) identify a diagnostic marker (e.g., urine TGFbeta levels) that will allow prediction of the progression of disease in target organs, b) make use of novel conditional, tissue-specific TGFb signaling knockout mice to investigate the mechanisms that cause matrix deposition and tissue damage, and c) explore alternative treatment strategies for preventing organ damage in lupus.
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