SPARC IS EXPRESSED IN RENAL INTERSTITIAL FIBROSIS AND IN RENAL VASCULAR INJURY

Tubulointerstitial inflammation and fibrosis are critical determinants for renal function and prognosis in a variety of human nephropathies. Yet. the pathophysiology of the injury remains obscure. We investigat ed the expression of SPARC (secreted protein acidic and rich in cystei ne) by immunohistochemistry and in situ hybridization in experimental models characterized by tubulointerstitial fibrosis and matrix expansi on in rats. SPARC is a secreted glycoprotein that has been demonstrate d to affect cellular interaction with matrix proteins, modulate cell p roliferation, hind to and!or inhibit growth factors such as PDGF and b FGF, and regulate angiogenesis, Interstitial expression of SPARC was m ost prominent in passive Heyman nephritis (PHN), chronic cyclosporine A (CsA) nephropathy, and the remnant kidney model and, to a lesser ext ent, in angiotensin II (Ang II)-infused animals. SPARC protein and mRN A were substantially increased at sites of tubulointerstitial fibrosis matrix expansion. In the PHN model. SPARC protein was expressed by in terstitial fibroblasts that also produced alpha-smooth muscle actin (' 'myofibroblasts'') and correlated both temporally (r = 0.97) and spati ally with sites of type I collagen deposition. Interstitial cell proli feration preceded the development of interstitial fibrosis, and maxima l SPARC expression (d15) coincided with the initial decline in interst itial proliferation. In the Ang II-infusion model, which is characteri zed by arteriolopathy and tubulointerstitial injury, an increase in SP ARC protein and mRNA was also seen in injured blood vessels. SPARC was shown to be expressed by vascular smooth muscle cells and also by cel ls in the adventitia of hypertrophied arteries. In summary. SPARC was transiently expressed by interstitial fibroblasts at sites of tubuloin terstitial injury and fibrosis, and by smooth muscle cells and cells i n the adventitia of injured arteries in the An II-model. In addition t o its proposed role in extracellular matrix deposition, the antiprolif erative properties of SPARC might contribute to the resolution of inte rstitial fibroblast proliferation in the PHN model.