Monocytes may promote myofibroblast accumulation and apoptosis in Alport renal fibrosis

Kathyrn D. Rodgers, Velidi Rao, Daniel T. Meehan, Nicole Fager, Philip Gotwals, Sarah T. Ryan, Victor Koteliansky, Ryoichi Nemori, Dominic E Cosgrove

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Background. In interstitial fibrosis, monocytes and myofibroblasts have been directly implicated in scarring, apoptosis, and tissue necrosis. While much has been done to explore the role of these cell types individually in fibrosis, the interactive dependency of monocytes and myofibroblasts has been only marginally explored. Methods. Alport mice were treated or not with a soluble receptor inhibitor for transforming growth factor-β1 (TGF-β1), which was previously shown to inhibit the accumulation of myofibroblasts, but not monocytes, in the tubulointerstitium. Kidneys were examined for fibrosis using several matrix markers, TGF-β1 mRNA expression by in situ hybridization, apoptosis using the terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL) assay, expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPS) by dual immunofluorescence microscopy, MMP activity by gelatin and in situ zymography, MMP mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR), and basement membrane degradation by dual immunofluorescence confocal microscopy and electron microscopy. Results. Treated mice showed a markedly reduced accumulation of matrix proteins. Tissue monocytes express TGF-β1 mRNA, and TGF-β1 is required for myofibroblast accumulation. The number of apoptotic cells was not influenced by TGF-β1 inhibition. Monocytes express MMP-2, MMP-9, TIMP-2, and TIMP-3. MMP activity and mRNA expression is equally up regulated in treated and untreated Alport mice. Tubular basement membranes (TBM) around clusters of monocytes are notably degraded. TGF-β1 inhibition does not extend the life of Alport mice. Conclusion. These studies demonstrate that monocytes may influence myofibroblast accumulation via TGF-β1, and that monocytes, and not myofibroblasts, are associated with tubular atrophy in Alport mice. Elevated MMP expression and activity is associated with TBM destruction near monocytes clusters, suggesting an anoikis mechanism may contribute to apoptosis in this model.

Original languageEnglish (US)
Pages (from-to)1338-1355
Number of pages18
JournalKidney International
Volume63
Issue number4
DOIs
StatePublished - Apr 1 2003

Fingerprint

Myofibroblasts
Monocytes
Transforming Growth Factors
Fibrosis
Apoptosis
Kidney
Matrix Metalloproteinases
Basement Membrane
Messenger RNA
Fluorescence Microscopy
Anoikis
Tissue Inhibitor of Metalloproteinase-3
Tissue Inhibitor of Metalloproteinases
Tissue Inhibitor of Metalloproteinase-2
Uridine Triphosphate
Matrix Metalloproteinase Inhibitors
DNA Nucleotidylexotransferase
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Gelatin

Keywords

  • Alport syndrome
  • Fibrosis
  • Kidney
  • Monocyte

ASJC Scopus subject areas

  • Nephrology

Cite this

Monocytes may promote myofibroblast accumulation and apoptosis in Alport renal fibrosis. / Rodgers, Kathyrn D.; Rao, Velidi; Meehan, Daniel T.; Fager, Nicole; Gotwals, Philip; Ryan, Sarah T.; Koteliansky, Victor; Nemori, Ryoichi; Cosgrove, Dominic E.

In: Kidney International, Vol. 63, No. 4, 01.04.2003, p. 1338-1355.

Research output: Contribution to journalArticle

Rodgers, KD, Rao, V, Meehan, DT, Fager, N, Gotwals, P, Ryan, ST, Koteliansky, V, Nemori, R & Cosgrove, DE 2003, 'Monocytes may promote myofibroblast accumulation and apoptosis in Alport renal fibrosis', Kidney International, vol. 63, no. 4, pp. 1338-1355. https://doi.org/10.1046/j.1523-1755.2003.00871.x
Rodgers, Kathyrn D. ; Rao, Velidi ; Meehan, Daniel T. ; Fager, Nicole ; Gotwals, Philip ; Ryan, Sarah T. ; Koteliansky, Victor ; Nemori, Ryoichi ; Cosgrove, Dominic E. / Monocytes may promote myofibroblast accumulation and apoptosis in Alport renal fibrosis. In: Kidney International. 2003 ; Vol. 63, No. 4. pp. 1338-1355.
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abstract = "Background. In interstitial fibrosis, monocytes and myofibroblasts have been directly implicated in scarring, apoptosis, and tissue necrosis. While much has been done to explore the role of these cell types individually in fibrosis, the interactive dependency of monocytes and myofibroblasts has been only marginally explored. Methods. Alport mice were treated or not with a soluble receptor inhibitor for transforming growth factor-β1 (TGF-β1), which was previously shown to inhibit the accumulation of myofibroblasts, but not monocytes, in the tubulointerstitium. Kidneys were examined for fibrosis using several matrix markers, TGF-β1 mRNA expression by in situ hybridization, apoptosis using the terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL) assay, expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPS) by dual immunofluorescence microscopy, MMP activity by gelatin and in situ zymography, MMP mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR), and basement membrane degradation by dual immunofluorescence confocal microscopy and electron microscopy. Results. Treated mice showed a markedly reduced accumulation of matrix proteins. Tissue monocytes express TGF-β1 mRNA, and TGF-β1 is required for myofibroblast accumulation. The number of apoptotic cells was not influenced by TGF-β1 inhibition. Monocytes express MMP-2, MMP-9, TIMP-2, and TIMP-3. MMP activity and mRNA expression is equally up regulated in treated and untreated Alport mice. Tubular basement membranes (TBM) around clusters of monocytes are notably degraded. TGF-β1 inhibition does not extend the life of Alport mice. Conclusion. These studies demonstrate that monocytes may influence myofibroblast accumulation via TGF-β1, and that monocytes, and not myofibroblasts, are associated with tubular atrophy in Alport mice. Elevated MMP expression and activity is associated with TBM destruction near monocytes clusters, suggesting an anoikis mechanism may contribute to apoptosis in this model.",
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AU - Rodgers, Kathyrn D.

AU - Rao, Velidi

AU - Meehan, Daniel T.

AU - Fager, Nicole

AU - Gotwals, Philip

AU - Ryan, Sarah T.

AU - Koteliansky, Victor

AU - Nemori, Ryoichi

AU - Cosgrove, Dominic E

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N2 - Background. In interstitial fibrosis, monocytes and myofibroblasts have been directly implicated in scarring, apoptosis, and tissue necrosis. While much has been done to explore the role of these cell types individually in fibrosis, the interactive dependency of monocytes and myofibroblasts has been only marginally explored. Methods. Alport mice were treated or not with a soluble receptor inhibitor for transforming growth factor-β1 (TGF-β1), which was previously shown to inhibit the accumulation of myofibroblasts, but not monocytes, in the tubulointerstitium. Kidneys were examined for fibrosis using several matrix markers, TGF-β1 mRNA expression by in situ hybridization, apoptosis using the terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL) assay, expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPS) by dual immunofluorescence microscopy, MMP activity by gelatin and in situ zymography, MMP mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR), and basement membrane degradation by dual immunofluorescence confocal microscopy and electron microscopy. Results. Treated mice showed a markedly reduced accumulation of matrix proteins. Tissue monocytes express TGF-β1 mRNA, and TGF-β1 is required for myofibroblast accumulation. The number of apoptotic cells was not influenced by TGF-β1 inhibition. Monocytes express MMP-2, MMP-9, TIMP-2, and TIMP-3. MMP activity and mRNA expression is equally up regulated in treated and untreated Alport mice. Tubular basement membranes (TBM) around clusters of monocytes are notably degraded. TGF-β1 inhibition does not extend the life of Alport mice. Conclusion. These studies demonstrate that monocytes may influence myofibroblast accumulation via TGF-β1, and that monocytes, and not myofibroblasts, are associated with tubular atrophy in Alport mice. Elevated MMP expression and activity is associated with TBM destruction near monocytes clusters, suggesting an anoikis mechanism may contribute to apoptosis in this model.

AB - Background. In interstitial fibrosis, monocytes and myofibroblasts have been directly implicated in scarring, apoptosis, and tissue necrosis. While much has been done to explore the role of these cell types individually in fibrosis, the interactive dependency of monocytes and myofibroblasts has been only marginally explored. Methods. Alport mice were treated or not with a soluble receptor inhibitor for transforming growth factor-β1 (TGF-β1), which was previously shown to inhibit the accumulation of myofibroblasts, but not monocytes, in the tubulointerstitium. Kidneys were examined for fibrosis using several matrix markers, TGF-β1 mRNA expression by in situ hybridization, apoptosis using the terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL) assay, expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPS) by dual immunofluorescence microscopy, MMP activity by gelatin and in situ zymography, MMP mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR), and basement membrane degradation by dual immunofluorescence confocal microscopy and electron microscopy. Results. Treated mice showed a markedly reduced accumulation of matrix proteins. Tissue monocytes express TGF-β1 mRNA, and TGF-β1 is required for myofibroblast accumulation. The number of apoptotic cells was not influenced by TGF-β1 inhibition. Monocytes express MMP-2, MMP-9, TIMP-2, and TIMP-3. MMP activity and mRNA expression is equally up regulated in treated and untreated Alport mice. Tubular basement membranes (TBM) around clusters of monocytes are notably degraded. TGF-β1 inhibition does not extend the life of Alport mice. Conclusion. These studies demonstrate that monocytes may influence myofibroblast accumulation via TGF-β1, and that monocytes, and not myofibroblasts, are associated with tubular atrophy in Alport mice. Elevated MMP expression and activity is associated with TBM destruction near monocytes clusters, suggesting an anoikis mechanism may contribute to apoptosis in this model.

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KW - Fibrosis

KW - Kidney

KW - Monocyte

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