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June 13, 2013AJP Renal Physiology

TGF-β/Smad3 activates mammalian target of rapamycin complex-1 to promote collagen production by increasing HIF-1α expression

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Authors

BRBenaya Rozen‐ZviTel Aviv UniversityTHTomoko HayashidaAmgen (United States)SHSusan C. HubchakNorthwestern University

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Implication

In vitro study demonstrates that TGF-β and Smad3 activate mTORC1 to stimulate HIF-1α-driven collagen production in human mesangial cells, highlighting a key axis in kidney fibrosis.

Key Points

  • To investigate the role of mTORC1 activation and its interaction with Smad3 and HIF-1α in driving TGF-β-mediated collagen synthesis in kidney cells.
  • Cultured human mesangial cells were stimulated with TGF-β in the presence or absence of Smad3 shRNA knockdown and Smad3 overexpression plasmids.
  • Inhibited mTORC1 activity using rapamycin or Raptor-targeted shRNA, and stimulated mTORC1 using constitutively active Rheb.
  • Measured COL1A2 promoter activity, type I collagen protein expression, hypoxia-responsive element (HRE) reporter activity, and HIF-1α protein abundance.
  • TGF-β increased mTORC1 activity in human mesangial cells through a TGF-β receptor- and Smad3-dependent mechanism.
  • Pharmacological or genetic inhibition of mTORC1 suppressed TGF-β-induced COL1A2 promoter activity, collagen I protein accumulation, and HIF-1α expression.
  • Overexpression of Smad3 enhanced HIF-1α expression via mTORC1, while exogenous HIF-1α overexpression completely bypassed mTORC1 inhibition to restore collagen synthesis.

Cite This Study

Rozen‐Zvi et al. (2013) studied this question.

synapsesocial.com/papers/6a71063ca528af2d65c3de5ahttps://doi.org/10.1152/ajprenal.00215.2013
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