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Oncostatin M inhibits TGF-β1-induced CTGF expression via STAT3 in human proximal tubular cells

Rita Sarközi1, Kathrin Flucher, Viktoria Maria Haller

  • 1Department of Internal Medicine IV, Nephrology and Hypertension, Innsbruck Medical University, Innsbruck, Austria.

Biochemical and Biophysical Research Communications
|July 21, 2012
PubMed

Insights

Oncostatin M (OSM) inhibits kidney fibrosis by suppressing connective tissue growth factor (CTGF) expression, primarily through the STAT3 signaling pathway. This finding offers a potential therapeutic mechanism for protecting against tubulointerstitial damage in kidney disease.

Area of Science:

  • Molecular Biology
  • Renal Pathophysiology
  • Cell Signaling

Background:

  • Matricellular proteins, including connective tissue growth factor (CTGF/CCN2), are key mediators in tubulointerstitial fibrosis and kidney disease progression.
  • CTGF is implicated in both glomerular and tubulointerstitial fibrosis in progressive kidney diseases.
  • Oncostatin M (OSM) has been identified as a potent inhibitor of transforming growth factor-beta 1 (TGF-β1)-induced CTGF expression in human proximal tubular cells (PTCs).

Purpose of the Study:

  • To investigate the signaling mechanisms by which TGF-β1 and OSM regulate CTGF mRNA expression in human proximal tubular HK-2 cells.
  • To elucidate the specific roles of SMAD and STAT signaling pathways in mediating the effects of TGF-β1 and OSM on CTGF expression.

Main Methods:

  • Utilized siRNA-mediated gene silencing to investigate the involvement of SMAD3, SMAD2, STAT1, and STAT3 in CTGF mRNA regulation.
  • Stimulated human proximal tubular HK-2 cells with TGF-β1 and OSM to analyze time-dependent effects on CTGF mRNA expression.
  • Assessed basal and TGF-β1-induced CTGF mRNA levels following STAT1 and STAT3 knockdown.

Main Results:

  • TGF-β1-induced CTGF mRNA expression was partially dependent on SMAD3, but not SMAD2.
  • OSM exhibited a dual effect: transient induction of CTGF mRNA at early time points (15 min to 1h) and significant suppression of basal and TGF-β1-induced CTGF mRNA at later time points.
  • STAT3 knockdown, but not STAT1 knockdown, prevented the OSM-mediated suppression of both basal and TGF-β1-induced CTGF mRNA upregulation, indicating STAT3's crucial role.

Conclusions:

  • The inhibitory effect of OSM on TGF-β1-induced CTGF mRNA expression is predominantly mediated by the STAT3 signaling pathway.
  • These findings reveal a signaling mechanism through which OSM may exert protective effects against tubulointerstitial fibrosis.
  • OSM's modulation of CTGF expression via STAT3 presents a potential therapeutic target for mitigating kidney disease progression.

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