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Nephrol Dial Transplant (2003) 18: 2240-2247
© 2003 European Renal Association-European Dialysis and Transplant Association

Original Article

Modulation of angiotensin II-mediated signalling by heparan sulphate glycosaminoglycans

Hannes Köppel1, Benito A. Yard1, Michael Christ2, Martin Wehling2 and Fokko J. van der Woude1

1V. Medizinische Klinik and 2Institüt für Klinische Pharmakologie, Klinikum Mannheim, University of Heidelberg, Mannheim, Germany

Correspondence and offprint requests to: Dr Hannes Köppel, V. Medizinische Universitätsklinik, Klinikum Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany. Email: KoeppelH{at}verw.ma.uni-heidelberg.de

Background. Heparin and angiotensin-converting enzyme inhibitors can be used as a therapeutic option in diabetic nephropathy (DN). Although the mode of action is poorly understood, both agents may retard the progression of DN. Previously, we demonstrated that angiotensin II (Ang II) has an inhibitory effect on the production of heparan sulphate proteoglycan (HSPG) in mesangial cells (MCs). We have now studied the influence of heparin on the Ang II-induced intracellular Ca2+ release and activation of nuclear factor kappa B (NF-{kappa}B).

Methods. Human MCs were isolated from renal cortex and cultivated to measure Ca2+ influx and NF-{kappa}B activation.

Results. Stimulation of MCs with 100 nM Ang II resulted in a rapid increase in the intracellular Ca2+ concentration ([Ca2+]i), followed by a decline to baseline level. The addition of heparin resulted in an oscillatory pattern of Ca2+ influxes upon Ang II stimulation. Whereas the rapid increase in [Ca2+]i was most likely due to release from intracellular stores, oscillations in [Ca2+]i were dependent on the presence of extracellular Ca2+. Heparin alone did not induce Ca2+ influx. Both the initial increase and the subsequent oscillations in [Ca2+]i could be blocked by losartan. In MCs with chemically or enzymatically altered membrane-associated heparan sulphate glycosaminoglycan (HS-GAG), Ang II stimulation resulted in [Ca2+]i oscillations. Interestingly, in these cells, the addition of heparin or GAG completely prevented [Ca2+]i oscillations. Heparin inhibited NF-{kappa}B activation in Ang II-stimulated MCs that expressed either normal or chemically altered GAG.

Conclusions. These findings suggest that alterations in HS-GAG chemistry or metabolism under pathological conditions, such as DN, may have direct functional consequences for the local effect of Ang II.

Keywords: angiotensin II; Ca2+ signalling; heparan sulphate glycosaminoglycan; heparin; mesangial cells; NF-{kappa}B


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U. Benck, S. Haeckel, J. H. Clorius, and F. J. van der Woude
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