EXTRACELLULAR MATRIX IN RENAL FIBROSIS

Vanderbilt University, Nashville TN

Investigators

Linked publications & trials

Abstract

Description (provided by applicant) Transforming growth factor-beta 1 (TGFbeta) has been implicated as a key molecule in fibrosis, and its expression is increased in numerous fibrotic conditions. The relationship of TGFbeta to other profibrotic mechanisms, such as angiotensin and plasminogen activator inhibitor-1 (PAI-1), and the differential role of infiltrating versus parenchymal cells are complex. TGFbeta can be locally activated by alphavbeta6, which is an integrin heterodimer that is expressed in epithelia in lung, skin and kidney and mediates cleavage of TGFbeta from latency associated peptide. Mice deficient in avB6 lack the ability to activate local TGFbeta through this alphavbeta6 integrin dependent mechanism and had marked protection against fibrosis in the unilateral ureteral obstruction model, with decreased PAI-1 expression, despite robust infiltration of macrophages. A full fibrotic response was restored by infusion of angiotensin or aldosterone, together with restoration of local increase of PAI-1. These projects will examine the TGFbeta1 dependent and independent mechanisms of fibrosis. We hypothesize that PAI-1 induction occurs even in the absence of local TGFbeta, and that PAI-1 by itself can effect fibrosis. We further hypothesize that both parenchymal and infiltrating cell mechanisms are necessary for full fibrotic response. We postulate that injury promotes epithelial-mesenchymal transdifferentiation, and that inadequate macrophage clearance of apoptotic cells both contribute to fibrosis. We will use the alphavbeta6 knockout mouse and bone marrow transplant, to experimentally manipulate parenchymal versus infiltrating cells combined with pharmacological manipulations, to determine mechanisms of interstitial fibrosis.