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NDT Advance Access originally published online on May 16, 2006
Nephrology Dialysis Transplantation 2006 21(9):2417-2424; doi:10.1093/ndt/gfl230
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Experimental Nephrology

The role of the {alpha}-1 adrenoceptor in modulating human mesangial cell matrix production

Izabella Z. A. Pawluczyk, Samita R. Patel and Kevin P. G. Harris

John Walls Renal Unit, Leicester General Hospital and Department of Infection, Immunity and Inflammation, University of Leicester, UK

Correspondence and offprint requests to: Dr I. Z. A. Pawluczyk, John Walls Renal Unit, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK. Email: izap1{at}le.ac.uk

Background. The sympathetic nervous system is frequently activated in hypertension and may modify various aspects of renal function. Whether modulation of the sympathetic nervous system directly influences the development of renal fibrosis is yet to be established. The current study investigates the role of the {alpha}-1 adrenoceptor on human mesangial cell scarring.

Methods. Human mesangial cells were injured with macrophage-conditioned medium (MPCM) and treated with doxazosin for 1 or 3 days.

Results. {alpha}-1 Adrenoceptor antagonist doxazosin of 2 µmol/l reduced fibronectin protein in MPCM-injured female mesangial cells by 31 ± 1.03% (P < 0.001) and by 9.5 ± 0.3% (P = 0.01) in male mesangial cells. The differential response between sexes was significant (P = 0.004). {alpha}-1B Adrenoceptors were detected in human mesangial cells by reverse transcription-polymerase chain reaction with expression in female cells being 87% higher than in males (P = 0.04). Injury with MPCM reduced {alpha}-1B adrenoceptor mRNA expression in both cell types. Doxazosin had no effect on the protein levels of transforming growth factor-ß (TGF-ß) or interleukin-1ß (IL-1ß), however, a small reduction in tumour necrosis factor-{alpha} (TNF-{alpha}) levels was observed. Doxazosin had no effect on the modulators of matrix turnover matrix metalloproteinases MMP3, MMP9 and tissue inhibitor of matrix metalloproteinases (TIMP-1), although a significant reduction in tissue plasminogen activator (tPA); (36.5 ± 2.6%, P < 0.001) was observed. Doxazosin caused an up-regulation of kallikrein expression, both at mRNA and protein levels. Co-treatment with the bradykinin B2 receptor antagonist HOE140 was able to attenuate the effects of doxazosin treatment on fibronectin levels.

Conclusion. These data suggest that inhibition of {alpha}-1B adrenoceptors in mesangial cells exerts an anti-fibrotic effect in a sex-specific manner via modulation of the kallikrein–kinin/plasminogen activator system.

Keywords: {alpha}-1 adrenoceptor; fibronectin; kallikrein; mesangial cells

Parts of this article were presented in abstract form at the annual American Society of Nephrology Meeting in St Louis, 2004.


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