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Indoxyl Sulfate Aggravates Podocyte Damage through the TGF-β1/Smad/ROS Signalling Pathway

Miao Jia1, Lihua Lin1, Kang Xun1

  • 1Department of Nephrology, The People's Hospital of Suzhou New District, Suzhou, China.

Kidney & Blood Pressure Research
|May 12, 2024
PubMed
Abstract

Insights

Indoxyl sulphate (IS) worsens diabetic nephropathy by increasing oxidative stress and altering TGF-β1/Smad signaling in podocytes. This study reveals IS impacts key proteins, offering new therapeutic targets for diabetic kidney disease.

Area of Science:

  • Nephrology
  • Diabetology
  • Molecular Biology

Background:

  • Diabetic nephropathy is driven by hyperglycemia-induced reactive oxygen species (ROS) and transforming growth factor β1 (TGF-β1)/Smad signaling.
  • Indoxyl sulphate (IS), a gut-derived uremic toxin, exacerbates podocyte injury via oxidative stress and inflammation.
  • The precise role of TGF-β1 signaling in IS-induced podocyte damage in diabetic nephropathy remains incompletely understood.

Purpose of the Study:

  • To investigate the impact of Indoxyl Sulphate (IS) on podocyte injury markers.
  • To elucidate the involvement of reactive oxygen species (ROS) and the transforming growth factor β1 (TGF-β1)/Smad signaling pathway in IS-mediated podocyte damage.
  • To explore potential therapeutic strategies for diabetic nephropathy by understanding IS effects.

Main Methods:

  • Cultured differentiated rat podocytes in vitro.
  • Utilized quantitative real-time PCR (qRT-PCR) and Western blotting to measure protein and gene expression levels.
  • Manipulated TGF-β1 levels (silencing and overexpression), used a ROS inhibitor (acetylcysteine), and exposed cells to high glucose (HG) and IS.

Main Results:

  • High glucose (HG) conditions, when combined with TGF-β1 silencing or ROS inhibition, upregulated protective podocyte markers (nephrin, synaptopodin, CD2AP, SRGAP2a) and downregulated α-SMA.
  • Conversely, HG with TGF-β1 overexpression downregulated protective markers and upregulated α-SMA.
  • IS supplementation under HG conditions significantly reduced protective markers, altered Smad signaling components (Smad2/3, p-Smad2/3, Smad7), affected NOX4 expression, and increased ROS production.

Conclusions:

  • Indoxyl sulphate (IS) significantly contributes to podocyte damage in diabetic nephropathy.
  • IS modulates the expression of key podocyte proteins by regulating ROS production and the TGF-β1/Smad signaling pathway.
  • These findings offer novel theoretical support for developing treatments targeting IS, ROS, and TGF-β1/Smad pathways for diabetic nephropathy.
Keywords:
Indoxyl sulphatePodocyte damageROSTGF-β1/Smad signalling

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