Matrix accumulation in mesangial cells exposed to cyclosporine A requires a permissive genetic background

Alessia Fornoni, Oliver Lenz, Ivan Tack, Mylene Potier, Sharon Elliot, Liliane J. Striker, Gary E. Striker

Research output: Contribution to journalArticle

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Abstract

Background. Chronic nephrotoxicity is an important adverse effect of cyclosporine A (CsA) therapy. Tubulo-interstitial lesions and arteriolopathy are common histologic findings. Glomerular lesions are also described, but they are of variable severity. The aim of our study is to determine whether CsA has a direct effect on mesangial cells and whether the cellular response depends on the genetic background. Methods. We studied mesangial cells isolated from mice susceptible (ROP/Le-+Es1b/+Es1a, ROP) and resistant to glomerulosclerosis (B6SJLF1, C57). We previously showed that sclerosis-prone and sclerosis resistant phenotypes are maintained in vitro. We examined whether CsA exposure directly affected extra cellular matrix turnover in mesangial cells and whether the response is determined by the genetic background. Extracellular matrix synthesis and degradation were studied by proline incorporation, ELISA, reverse transcription-polymerase chain reaction, zymography, and reverse zymography. We chose a CsA dose that induced neither cytotoxicity nor apoptosis (1 μg/ml). Results. At the dose of 1 μg/ml total collagen accumulation was increased in ROP but not in C57 cells. Matrix metalloproteinase (MMP)-2 activity and mRNA levels were selectively decreased in ROP cells. CsA exposure did not affect tissue inhibitors of MMP (TIMP)-1 and -2 activity or TGF-β1 mRNA expression and protein synthesis in either cell line. Conclusion. CsA increases total collagen accumulation in mesangial cells from sclerosis-prone mice by decreasing MMP-2 activity, but does not affect cells from sclerosis-resistant mice. Thus, CsA directly affects mesangial cells, but only those with a permissive genetic background for glomerulosclerosis.

Original languageEnglish
Pages (from-to)587-593
Number of pages7
JournalTransplantation
Volume70
Issue number4
StatePublished - Aug 27 2000

Fingerprint

Mesangial Cells
Cyclosporine
Sclerosis
Matrix Metalloproteinase 2
Collagen
Messenger RNA
Matrix Metalloproteinase 1
Tissue Inhibitor of Metalloproteinase-1
Genetic Background
Proline
Reverse Transcription
Extracellular Matrix
Enzyme-Linked Immunosorbent Assay
Apoptosis
Phenotype
Cell Line
Polymerase Chain Reaction
ROP

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Matrix accumulation in mesangial cells exposed to cyclosporine A requires a permissive genetic background. / Fornoni, Alessia; Lenz, Oliver; Tack, Ivan; Potier, Mylene; Elliot, Sharon; Striker, Liliane J.; Striker, Gary E.

In: Transplantation, Vol. 70, No. 4, 27.08.2000, p. 587-593.

Research output: Contribution to journalArticle

Fornoni, Alessia ; Lenz, Oliver ; Tack, Ivan ; Potier, Mylene ; Elliot, Sharon ; Striker, Liliane J. ; Striker, Gary E. / Matrix accumulation in mesangial cells exposed to cyclosporine A requires a permissive genetic background. In: Transplantation. 2000 ; Vol. 70, No. 4. pp. 587-593.
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N2 - Background. Chronic nephrotoxicity is an important adverse effect of cyclosporine A (CsA) therapy. Tubulo-interstitial lesions and arteriolopathy are common histologic findings. Glomerular lesions are also described, but they are of variable severity. The aim of our study is to determine whether CsA has a direct effect on mesangial cells and whether the cellular response depends on the genetic background. Methods. We studied mesangial cells isolated from mice susceptible (ROP/Le-+Es1b/+Es1a, ROP) and resistant to glomerulosclerosis (B6SJLF1, C57). We previously showed that sclerosis-prone and sclerosis resistant phenotypes are maintained in vitro. We examined whether CsA exposure directly affected extra cellular matrix turnover in mesangial cells and whether the response is determined by the genetic background. Extracellular matrix synthesis and degradation were studied by proline incorporation, ELISA, reverse transcription-polymerase chain reaction, zymography, and reverse zymography. We chose a CsA dose that induced neither cytotoxicity nor apoptosis (1 μg/ml). Results. At the dose of 1 μg/ml total collagen accumulation was increased in ROP but not in C57 cells. Matrix metalloproteinase (MMP)-2 activity and mRNA levels were selectively decreased in ROP cells. CsA exposure did not affect tissue inhibitors of MMP (TIMP)-1 and -2 activity or TGF-β1 mRNA expression and protein synthesis in either cell line. Conclusion. CsA increases total collagen accumulation in mesangial cells from sclerosis-prone mice by decreasing MMP-2 activity, but does not affect cells from sclerosis-resistant mice. Thus, CsA directly affects mesangial cells, but only those with a permissive genetic background for glomerulosclerosis.

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