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Nitric oxide inhibition of transforming growth factor-beta and collagen synthesis in mesangial cells

P A Craven1, R K Studer, J Felder

  • 1Department of Medicine, University of Pittsburgh, Pennsylvania, USA. pcraven@unixs.cis.pitt.edu

Diabetes
|April 1, 1997
PubMed

Insights

High glucose increases protein kinase C (PKC) and transforming growth factor-beta1 (TGF-beta1) in mesangial cells. Nitric oxide (NO) suppresses these effects, suggesting a protective role in kidney disease.

Area of Science:

  • Nephrology
  • Cell Biology
  • Biochemistry

Background:

  • High glucose concentrations induce cellular changes in the kidney, contributing to diabetic nephropathy.
  • Transforming growth factor-beta1 (TGF-beta1) and collagen synthesis are key mediators of kidney damage in diabetes.
  • Protein kinase C (PKC) activity is implicated in the pathogenesis of diabetic complications.

Purpose of the Study:

  • To investigate the role of nitric oxide (NO) in modulating TGF-beta1 and collagen synthesis in mesangial cells under high glucose conditions.
  • To explore the signaling pathways involved, including PKC and cGMP.

Main Methods:

  • Mesangial cells (MCs) and glomerular capillary endothelial cells (GCECs) were cultured under varying glucose concentrations (5.6 vs. 30.0 mmol/l).
  • Effects of NO donors (SNAP), NO-inducing agents (IL-1beta), PKC inhibitors (GFX), and NO synthesis inhibitors (NMMA) were assessed.
  • TGF-beta1 mRNA, bioactive TGF-beta, collagen synthesis, and PKC activity were measured.
  • cGMP analogs and antagonists were used to investigate cGMP mediation.

Main Results:

  • High glucose (30.0 mmol/l) sustained increased PKC activity, TGF-beta1 mRNA, bioactive TGF-beta, and collagen synthesis.
  • Exogenous and endogenous NO (via SNAP and IL-1beta) suppressed TGF-beta and collagen synthesis induced by high glucose or phorbol ester.
  • NO's effects were not mediated by cGMP.
  • PKC inhibition mimicked NO's suppressive actions.
  • NMMA increased TGF-beta and collagen synthesis, while captopril inhibited them, with effects mediated by NO.

Conclusions:

  • Endogenous NO, particularly from GCECs, plays a crucial role in suppressing TGF-beta production and matrix protein synthesis in MCs.
  • NO acts as a protective factor against high glucose-induced kidney damage by inhibiting TGF-beta and collagen synthesis.
  • Targeting NO pathways may offer therapeutic strategies for diabetic nephropathy.

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