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Renal fibrosis is not reduced by blocking transforming growth factor-β signaling in matrix-producing interstitial cells.

Neelisetty S, Alford C, Reynolds K, Woodbury L, Nlandu-Khodo S, Yang H, Fogo AB, Hao CM, Harris RC, Zent R, Gewin L - Kidney Int. (2015)

Bottom Line: To address this, we deleted the TGF-β type II receptor in matrix-producing interstitial cells using two different inducible Cre models: COL1A2-Cre with a mesenchymal enhancer element and tenascin-Cre that targets medullary interstitial cells, and either the mouse unilateral ureteral obstruction or the aristolochic acid renal injury model.Renal interstitial cells lacking the TGF-β receptor had significantly impaired collagen I production, but, unexpectedly, overall tissue fibrosis was unchanged in the conditional knockouts after renal injury.Thus, abrogating TGF-β signaling in matrix-producing interstitial cells is not sufficient to reduce fibrosis after renal injury.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee, USA.

ABSTRACT
Transforming growth factor-β (TGF-β) strongly promotes renal tubulointerstitial fibrosis, but the cellular target that mediates its profibrotic actions has not been clearly identified. While in vitro data suggest that TGF-β-induced matrix production is mediated by renal fibroblasts, the role of these cells in TGF-β-dependent tubulointerstitial fibrosis following renal injury is not well defined. To address this, we deleted the TGF-β type II receptor in matrix-producing interstitial cells using two different inducible Cre models: COL1A2-Cre with a mesenchymal enhancer element and tenascin-Cre that targets medullary interstitial cells, and either the mouse unilateral ureteral obstruction or the aristolochic acid renal injury model. Renal interstitial cells lacking the TGF-β receptor had significantly impaired collagen I production, but, unexpectedly, overall tissue fibrosis was unchanged in the conditional knockouts after renal injury. Thus, abrogating TGF-β signaling in matrix-producing interstitial cells is not sufficient to reduce fibrosis after renal injury.

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Related in: MedlinePlus

Deleting TβRII in fibroblasts does not change GFP or PDGFRβ+ expression but does alter inflammation. (A–C) Flow cytometry was performed on kidneys 3 days after UUO from COL-Cre;WT and COL-Cre;Tgfbr2fl/fl mice to measure GFP+, PDGFRβ+, and F4/80+ with the isotype control (IgG2a) in Figure 2G used for both PDGFRβ and F4/80. The percentage of GFP+ (D), PDGFRβ+ (D), and F4/80+ (E) cells among viable single cells was measured among 5 COL-Cre;WT and 3 COL-Cre;Tgfbr2fl/fl mice (* for p<0.05).
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Figure 6: Deleting TβRII in fibroblasts does not change GFP or PDGFRβ+ expression but does alter inflammation. (A–C) Flow cytometry was performed on kidneys 3 days after UUO from COL-Cre;WT and COL-Cre;Tgfbr2fl/fl mice to measure GFP+, PDGFRβ+, and F4/80+ with the isotype control (IgG2a) in Figure 2G used for both PDGFRβ and F4/80. The percentage of GFP+ (D), PDGFRβ+ (D), and F4/80+ (E) cells among viable single cells was measured among 5 COL-Cre;WT and 3 COL-Cre;Tgfbr2fl/fl mice (* for p<0.05).

Mentions: TGF-β signaling can alter cellular proliferation and exert both pro- and anti-inflammatory effects depending upon the cellular milieu, so we investigated whether deleting TβRII in COL-Cre cells alters the number of MPIC or inflammation after UUO. There were no major changes in GFP+ or PDGFRβ+ expression between COL-Cre and COL-Cre;Tgfbr2fl/fl mice at 3 days after UUO (Figure 6A, 6B, 6D). Staining of F4/80, a macrophage marker, revealed a small but statistically significant increase in F4/80+ cells (14.8% to 19%) when TβRII was deleted using COL-Cre (Figure 6C, 6E). Thus, deleting TβRII using COL-Cre does not ameliorate fibrosis or alter the number of MPIC, but does increase F4/80 infiltration.


Renal fibrosis is not reduced by blocking transforming growth factor-β signaling in matrix-producing interstitial cells.

Neelisetty S, Alford C, Reynolds K, Woodbury L, Nlandu-Khodo S, Yang H, Fogo AB, Hao CM, Harris RC, Zent R, Gewin L - Kidney Int. (2015)

Deleting TβRII in fibroblasts does not change GFP or PDGFRβ+ expression but does alter inflammation. (A–C) Flow cytometry was performed on kidneys 3 days after UUO from COL-Cre;WT and COL-Cre;Tgfbr2fl/fl mice to measure GFP+, PDGFRβ+, and F4/80+ with the isotype control (IgG2a) in Figure 2G used for both PDGFRβ and F4/80. The percentage of GFP+ (D), PDGFRβ+ (D), and F4/80+ (E) cells among viable single cells was measured among 5 COL-Cre;WT and 3 COL-Cre;Tgfbr2fl/fl mice (* for p<0.05).
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Related In: Results  -  Collection

License
Show All Figures
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Figure 6: Deleting TβRII in fibroblasts does not change GFP or PDGFRβ+ expression but does alter inflammation. (A–C) Flow cytometry was performed on kidneys 3 days after UUO from COL-Cre;WT and COL-Cre;Tgfbr2fl/fl mice to measure GFP+, PDGFRβ+, and F4/80+ with the isotype control (IgG2a) in Figure 2G used for both PDGFRβ and F4/80. The percentage of GFP+ (D), PDGFRβ+ (D), and F4/80+ (E) cells among viable single cells was measured among 5 COL-Cre;WT and 3 COL-Cre;Tgfbr2fl/fl mice (* for p<0.05).
Mentions: TGF-β signaling can alter cellular proliferation and exert both pro- and anti-inflammatory effects depending upon the cellular milieu, so we investigated whether deleting TβRII in COL-Cre cells alters the number of MPIC or inflammation after UUO. There were no major changes in GFP+ or PDGFRβ+ expression between COL-Cre and COL-Cre;Tgfbr2fl/fl mice at 3 days after UUO (Figure 6A, 6B, 6D). Staining of F4/80, a macrophage marker, revealed a small but statistically significant increase in F4/80+ cells (14.8% to 19%) when TβRII was deleted using COL-Cre (Figure 6C, 6E). Thus, deleting TβRII using COL-Cre does not ameliorate fibrosis or alter the number of MPIC, but does increase F4/80 infiltration.

Bottom Line: To address this, we deleted the TGF-β type II receptor in matrix-producing interstitial cells using two different inducible Cre models: COL1A2-Cre with a mesenchymal enhancer element and tenascin-Cre that targets medullary interstitial cells, and either the mouse unilateral ureteral obstruction or the aristolochic acid renal injury model.Renal interstitial cells lacking the TGF-β receptor had significantly impaired collagen I production, but, unexpectedly, overall tissue fibrosis was unchanged in the conditional knockouts after renal injury.Thus, abrogating TGF-β signaling in matrix-producing interstitial cells is not sufficient to reduce fibrosis after renal injury.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee, USA.

ABSTRACT
Transforming growth factor-β (TGF-β) strongly promotes renal tubulointerstitial fibrosis, but the cellular target that mediates its profibrotic actions has not been clearly identified. While in vitro data suggest that TGF-β-induced matrix production is mediated by renal fibroblasts, the role of these cells in TGF-β-dependent tubulointerstitial fibrosis following renal injury is not well defined. To address this, we deleted the TGF-β type II receptor in matrix-producing interstitial cells using two different inducible Cre models: COL1A2-Cre with a mesenchymal enhancer element and tenascin-Cre that targets medullary interstitial cells, and either the mouse unilateral ureteral obstruction or the aristolochic acid renal injury model. Renal interstitial cells lacking the TGF-β receptor had significantly impaired collagen I production, but, unexpectedly, overall tissue fibrosis was unchanged in the conditional knockouts after renal injury. Thus, abrogating TGF-β signaling in matrix-producing interstitial cells is not sufficient to reduce fibrosis after renal injury.

Show MeSH
Related in: MedlinePlus