RENAL FIBROSIS

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Fibrosis in the kidney is an active process triggered by many forms of renal injury and it is associated with permanent loss of renal tissue, and therefore with poor outcome. We hypothesize that prevention of scarring would allow normal renal tissue to recover in most forms of renal injury. We therefore need to understand collagen metabolism in the normal and abnormal kidney so that strategies can be developed that would inhibit or retard the scarring process. To address this question we have analyzed in detail collagen metabolism in a rabbit model of anti-GBM disease that reproducibly goes on to fibrosis both in interstitial and glomerular compartments. Analysis using in situ hybridization for rabbit alpha2(I) procollagen mRNA indicates that a previously unrecognized cell, the vascular adventitial cell (VAC), is a major cell responsible for the scarring process in the model. To confirm this hypothesis and proposed in this application we will determine whether other collagen mRNAs are distributed in a similar manner during evolution of the scarring process in the model. We will characterize and identify the chemotactic factors responsible for attracting the VAC from the perivascular adventitial compartment out into the interstitium and thence to the periglomerular region from where it gains access to Bowman's space. We will characterize the VAC from normal and scarring kidney so that we can understand what factors regulate its' collagen synthesis, chemotaxis and cell division. We will determine in vivo whether depletion of TGF-beta, which we have previously shown to be the major factor driving collagen synthesis in the model, prevents scarring and preserves renal function. Finally we will test the idea that we can predict which individuals will develop severe scarring by measuring mRNA levels for collagens early in the sequence of events before scar formation has occurred. If we can predict who will go on to scar, and develop strategies that prevent scarring, we will have begun to develop the basis for an anti-scarring strategy that could be applied to severe forms of inflammatory diseases in man, including severe glomerulonephritis, interstitial nephritis and transplant rejection, that commonly result in permanent loss of renal structure and function.