Purinergic modulation of mesangial extracellular matrix production: role in diabetic and other glomerular diseases.

Abstract

BACKGROUND:

Extracellular adenosine triphosphate (ATP) (eATP) mediates several biologic activities via purinergic P2 receptors (P2Rs). This study aimed at (1) evaluating the role of the purinergic system in modulating mesangial extracellular matrix (ECM) and transforming growth factor-beta (TGF-beta) production and (2) its contribution to diabetes-induced mesangial ECM accumulation.

METHODS:

Rat mesangial cells were grown in normal glucose (5.5 mmol/L) or high glucose (30 mmol/L) containing media and probed with purinergic agonists and antagonists for the assessment of the expression pattern and function of P2Rs; release of ATP and activity of ectoATPases; and changes in ECM and TGF-beta expression.

RESULTS:

Cells cultured in normal glucose and high glucose expressed similar amounts of functional P2Rs of the P2X(2), P2X(3), P2X(4), P2X(5), P2X(7), P2Y(1), P2Y(2), P2Y(4), and P2Y(6) subtypes. Levels of eATP were higher in high glucose vs. normal glucose, with unchanged ectoATPase activity. The ATP-hydrolyzing enzymes hexokinase or apyrase reduced ECM and TGF-beta production from cells grown in high glucose, but not normal glucose. Under both normal glucose and high glucose conditions, ATP and the P2X(7) agonist benzoylbenzoylATP increased dose-dependently ECM and TGF-beta production, whereas the P2Y agonist uridine triphosphate (UTP) produced the opposite effect. The P2X(7) inhibitor oxidized ATP attenuated the ECM and TGF-beta up-regulation induced by ATP and, to a lesser extent, that caused by high glucose. A TGF-beta neutralizing antibody also prevented ATP-induced ECM up-regulation.

CONCLUSION:

These data indicate a role for eATP in regulating ECM production via TGF-beta and suggest that P2XRs and P2YRs differentially modulate this process. An increased ATP release induced by hyperglycemia might contribute to mesangial matrix expansion occurring in diabetes.

• Authors: Anna Solini, Carla Iacobini, Carlo Ricci, Paola Chiozzi, Lorena Amadio, Flavia Pricci, Umberto Di Mario, Francesco Di Virgilio, Giuseppe Pugliese
• Journal: Kidney international (Kidney Int) Vol. 67 Issue 3 Pg. 875-85 (Mar 2005) ISSN: 0085-2538 [Print] United States
• PMID: 15698427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Extracellular Matrix Proteins
• Receptors, Purinergic P2
• Transforming Growth Factor beta
• Adenosine Triphosphate
• Adenosine Triphosphatases
• ectoATPase

Topics

• Adenosine Triphosphatases
• Adenosine Triphosphate (physiology)
• Animals
• Cells, Cultured
• Diabetes Mellitus, Experimental (metabolism)
• Extracellular Matrix Proteins (biosynthesis)
• Glomerular Mesangium (metabolism)
• Kidney Diseases (metabolism)
• Rats
• Receptors, Purinergic P2 (physiology)
• Transforming Growth Factor beta (biosynthesis)