Interleukin-1beta induces human proximal tubule cell injury, alpha-smooth muscle actin expression and fibronectin production

Vesey, David A., Cheung, Cathrine W.Y., Cuttle, Leila, Endre, Zoltan A., Gobe, Glenda, & Johnson, David W. (2002) Interleukin-1beta induces human proximal tubule cell injury, alpha-smooth muscle actin expression and fibronectin production. Kidney International, 62(1), pp. 31-40.

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Abstract

BACKGROUND

Tubulointerstitial lesions, characterized by tubular injury, interstitial fibrosis and the appearance of myofibroblasts, are the strongest predictors of the degree and progression of chronic renal failure. These lesions are typically preceded by macrophage infiltration of the tubulointerstitium, raising the possibility that these inflammatory cells promote progressive renal disease through fibrogenic actions on resident tubulointerstitial cells. The aim of the present study, therefore, was to investigate the potentially fibrogenic mechanisms of interleukin-1beta (IL-1beta), a macrophage-derived pro-inflammatory cytokine, on human proximal tubule cells (PTC).

METHODS

Confluent, quiescent, passage 2 PTC were established in primary culture from histologically normal segments of human renal cortex (N = 11) and then incubated in serum- and hormone-free media supplemented with either IL-1beta (0 to 4 ng/mL) or vehicle (control).

RESULTS

IL-1beta significantly enhanced fibronectin secretion by up to fourfold in a time- and concentration-dependent fashion. This was accompanied by significant (2.5- to 6-fold) increases in alpha-smooth muscle actin (alpha-SMA) expression, transforming growth factor beta (TGF-beta1) secretion, nitric oxide (NO) production, NO synthase 2 (NOS2) mRNA and lactate dehydrogenase (LDH) release. Cell proliferation was dose-dependently suppressed by IL-1beta. NG-methyl-l-arginine (L-NMMA; 1 mmol/L), a specific inhibitor of NOS, blocked NO production but did not alter basal or IL-1beta-stimulated fibronectin secretion. In contrast, a pan-specific TGF-beta neutralizing antibody significantly blocked the effects of IL-1beta on PTC fibronectin secretion (IL-1beta, 268.1 +/- 30.6 vs. IL-1beta+alphaTGF-beta 157.9 +/- 14.4%, of control values, P < 0.001) and DNA synthesis (IL-1beta 81.0 +/- 6.7% vs. IL-1beta+alphaTGF-beta 93.4 +/- 2.1%, of control values, P < 0.01).

CONCLUSION

IL-1beta acts on human PTC to suppress cell proliferation, enhance fibronectin production and promote alpha-smooth muscle actin expression. These actions appear to be mediated by a TGF-beta1 dependent mechanism and are independent of nitric oxide release.

Impact and interest:

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ID Code: 67220
Item Type: Journal Article
Refereed: Yes
Additional URLs:
Keywords: Actins/*analysis, Cell Division/drug effects, Cell Survival/drug effects, Cells, Cultured, DNA/biosynthesis, Female, Fibronectins/*biosynthesis, Humans, Interleukin-1/*toxicity, Kidney Tubules, Proximal/*drug effects/metabolism/pathology, Male, Middle Aged, Muscle, Smooth/metabolism, Nitric Oxide/biosynthesis, Nitric Oxide Synthase/genetics, Nitric Oxide Synthase Type II, Reactive Nitrogen Species/metabolism, Transforming Growth Factor beta/biosynthesis
DOI: 10.1046/j.1523-1755.2002.00401.x
ISSN: 0085-2538
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2002 International Society of Nephrology
Deposited On: 26 Feb 2014 23:51
Last Modified: 26 Feb 2014 23:51

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