MOLECULAR INSIGHTS INTO RENAL INTERSTITIAL FIBROSIS

Progressive interstitial fibrosis accompanied by loss of renal tubules and interstitial capillaries typifies all progressive renal diseases, Dynamic and complex, the process evidently overlaps with matrix remod eling; it may even be reversible, The interstitial fibrous tissue comp rises several normal and novel matrix proteins, proteoglycans, and gly coproteins. Interstitial myofibroblasts are a major site of matrix pro tein overproduction, although resident fibroblasts, tubular cells, and inflammatory cells may contribute. Inadequate matrix degradation also appears to contribute to the fibrogenic process, Two protease cascade s, the metalloproteinases and the plasminogen activator/ plasmin famil y of serine proteases, are implicated in the turnover of interstitial matrix proteins; upregulated expression of protease inhibitors has bee n observed in each. Increased tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1 levels suggest that the intrinsi c renal activity of the metalloproteinases and serine proteases are in hibited while matrix proteins accumulate in the interstitium. Several signals that may direct the interstitial fibrogenic process have been identified, but not yet proved to cause it. Upregulated expression of transforming growth factor beta-1, the proteotypic fibrogenic cytokine , has been observed in experimental and human models; it probably does not act alone, There may be supportive roles for platelet-derived gro wth factor, interleukin-1, basic fibroblast growth factor, angiotensin II, and endothelin-1, Although it is not known why interstitial fibro sis compromises renal function, atrophy of renal tubules may be pivota l. Ischemic necrosis and/or apoptosis may generate nonfunctioning atub ular and sclerotic glomeruli, Future studies must delineate the molecu lar basis of the differences between renal repair and renal destructio n by fibrosis, two processes that share many common features.