BACKGROUND: In proteinuric nephropathies with increasingly severe defects of the glomerular filtering barrier, interstitial fibrogenesis is a major effector of scarring. An early event in this process is the peritubular accumulation of myofibroblasts that express alpha-smooth muscle actin (alpha-SMA) and contribute to abnormal matrix production. Common trigger factors are poorly understood. Enhanced protein trafficking may play a role by up-regulating inflammatory and fibrogenic genes in proximal tubular cells. METHODS: The remnant kidney model in rats was used to (1) analyze interactions between activated proximal tubular cells, peritubular cells expressing the myofibroblast marker, and inflammatory cells at time intervals (days 7, 14, and 30) after surgery, and (2) evaluate the effects of angiotensin-converting enzyme inhibitor (ACEi) on protein trafficking, fibrogenic signaling, and alpha-SMA expression. RESULTS: Abnormal uptake of ultrafiltered proteins by proximal tubular cells (IgG staining) occurred at an early stage (day 7) and was subsequently associated with macrophage and alpha-SMA+ cell accumulation into the peritubular interstitium. alpha-SMA+ cells clustered with macrophages into the interstitium. These changes were associated with appearance of transforming growth factor-beta1 (TGF-beta1) mRNA in proximal tubular cells and in the infiltrating cells with time. At day 30, focal alpha-SMA staining also was found in the tubular cells and in peritubular endothelial cells on semithin ultracryosections. ACEi prevented both proteinuria and abnormal protein accumulation in tubular cells, as well as the inflammatory and fibrogenic reaction with peritubular alpha-SMA expression. CONCLUSIONS: Profibrogenic signaling from both proximal tubular cells on challenge with filtered protein and inflammatory cells is implicated as a key candidate trigger of progressive tubulointerstitial injury.
BACKGROUND: In proteinuric nephropathies with increasingly severe defects of the glomerular filtering barrier, interstitial fibrogenesis is a major effector of scarring. An early event in this process is the peritubular accumulation of myofibroblasts that express alpha-smooth muscle actin (alpha-SMA) and contribute to abnormal matrix production. Common trigger factors are poorly understood. Enhanced protein trafficking may play a role by up-regulating inflammatory and fibrogenic genes in proximal tubular cells. METHODS: The remnant kidney model in rats was used to (1) analyze interactions between activated proximal tubular cells, peritubular cells expressing the myofibroblast marker, and inflammatory cells at time intervals (days 7, 14, and 30) after surgery, and (2) evaluate the effects of angiotensin-converting enzyme inhibitor (ACEi) on protein trafficking, fibrogenic signaling, and alpha-SMA expression. RESULTS: Abnormal uptake of ultrafiltered proteins by proximal tubular cells (IgG staining) occurred at an early stage (day 7) and was subsequently associated with macrophage and alpha-SMA+ cell accumulation into the peritubular interstitium. alpha-SMA+ cells clustered with macrophages into the interstitium. These changes were associated with appearance of transforming growth factor-beta1 (TGF-beta1) mRNA in proximal tubular cells and in the infiltrating cells with time. At day 30, focal alpha-SMA staining also was found in the tubular cells and in peritubular endothelial cells on semithin ultracryosections. ACEi prevented both proteinuria and abnormal protein accumulation in tubular cells, as well as the inflammatory and fibrogenic reaction with peritubular alpha-SMA expression. CONCLUSIONS: Profibrogenic signaling from both proximal tubular cells on challenge with filtered protein and inflammatory cells is implicated as a key candidate trigger of progressive tubulointerstitial injury.
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