Proximal tubular cells promote fibrogenesis by TGF-β1-mediated induction of peritubular myofibroblasts

Mauro Abbate, Carla Zoja, Daniela Rottoli, Daniela Corna, Susanna Tomasoni, Giuseppe Remuzzi

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

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 α-smooth muscle actin (α-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 α-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 α-SMA + cell accumulation into the peritubular interstitium, α-SMA + cells clustered with macrophages into the interstitium. These changes were associated with appearance of transforming growth factor-β1 (TGF-β1) mRNA in proximal tubular cells and in the infiltrating cells with time. At day 30, focal α-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 α-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.

Original languageEnglish
Pages (from-to)2066-2077
Number of pages12
JournalKidney International
Volume61
Issue number6
DOIs
Publication statusPublished - 2002

Fingerprint

Myofibroblasts
Transforming Growth Factors
Protein Transport
Angiotensin-Converting Enzyme Inhibitors
Macrophages
Staining and Labeling
Proteins
Proteinuria
Cicatrix
Smooth Muscle
Actins
Endothelial Cells
Immunoglobulin G

Keywords

  • α-smooth muscle actin
  • Angiotensin converting enzyme inhibitor
  • Fibrosis
  • Macrophage
  • Progressive renal disease
  • Proteinuria
  • Tubulointerstitial injury

ASJC Scopus subject areas

  • Nephrology

Cite this

Proximal tubular cells promote fibrogenesis by TGF-β1-mediated induction of peritubular myofibroblasts. / Abbate, Mauro; Zoja, Carla; Rottoli, Daniela; Corna, Daniela; Tomasoni, Susanna; Remuzzi, Giuseppe.

In: Kidney International, Vol. 61, No. 6, 2002, p. 2066-2077.

Research output: Contribution to journalArticle

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abstract = "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 α-smooth muscle actin (α-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 α-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 α-SMA + cell accumulation into the peritubular interstitium, α-SMA + cells clustered with macrophages into the interstitium. These changes were associated with appearance of transforming growth factor-β1 (TGF-β1) mRNA in proximal tubular cells and in the infiltrating cells with time. At day 30, focal α-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 α-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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T1 - Proximal tubular cells promote fibrogenesis by TGF-β1-mediated induction of peritubular myofibroblasts

AU - Abbate, Mauro

AU - Zoja, Carla

AU - Rottoli, Daniela

AU - Corna, Daniela

AU - Tomasoni, Susanna

AU - Remuzzi, Giuseppe

PY - 2002

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N2 - 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 α-smooth muscle actin (α-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 α-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 α-SMA + cell accumulation into the peritubular interstitium, α-SMA + cells clustered with macrophages into the interstitium. These changes were associated with appearance of transforming growth factor-β1 (TGF-β1) mRNA in proximal tubular cells and in the infiltrating cells with time. At day 30, focal α-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 α-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.

AB - 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 α-smooth muscle actin (α-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 α-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 α-SMA + cell accumulation into the peritubular interstitium, α-SMA + cells clustered with macrophages into the interstitium. These changes were associated with appearance of transforming growth factor-β1 (TGF-β1) mRNA in proximal tubular cells and in the infiltrating cells with time. At day 30, focal α-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 α-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.

KW - α-smooth muscle actin

KW - Angiotensin converting enzyme inhibitor

KW - Fibrosis

KW - Macrophage

KW - Progressive renal disease

KW - Proteinuria

KW - Tubulointerstitial injury

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