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

Vesey, D. A., Cheung, C. W. Y., Cuttle, L., Endre, Z. A., Gobe, G. and Johnson, D. W. (2002) Interleukin-1 beta induces human proximal tubule cell injury, alpha-smooth muscle actin expression and fibronectin production. Kidney International, 62 1: 31-40. doi:10.1046/j.1523-1755.2002.00401.x


Author Vesey, D. A.
Cheung, C. W. Y.
Cuttle, L.
Endre, Z. A.
Gobe, G.
Johnson, D. W.
Title Interleukin-1 beta induces human proximal tubule cell injury, alpha-smooth muscle actin expression and fibronectin production
Formatted title
Interleukin-1β induces human proximal tubule cell injury, α-smooth muscle actin expression and fibronectin production
Journal name Kidney International   Check publisher's open access policy
ISSN 0085-2538
Publication date 2002-07-01
Sub-type Article (original research)
DOI 10.1046/j.1523-1755.2002.00401.x
Volume 62
Issue 1
Start page 31
End page 40
Total pages 10
Editor S. Klahr
S.S. Neilson
M. Hammerman
Place of publication New York
Publisher NPG
Collection year 2002
Language eng
Subject C1
730115 Urogenital system and disorders
110312 Nephrology and Urology
Formatted abstract
Interleukin-1β induces human proximal tubule cell injury, α-smooth muscle actin expression and fibronectin production.

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-1β (IL-1β), 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-1β (0 to 4 ng/mL) or vehicle (control).

Results
IL-1β 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 α-smooth muscle actin (α-SMA) expression, transforming growth factor β (TGF-β1) secretion, nitric oxide (NO) production, NO synthase 2 (NOS2) mRNA and lactate dehydrogenase (LDH) release. Cell proliferation was dose-dependently suppressed by IL-1β. NG-methyl-L-arginine (L-NMMA; 1 mmol/L), a specific inhibitor of NOS, blocked NO production but did not alter basal or IL-1β–stimulated fibronectin secretion. In contrast, a pan-specific TGF-β neutralizing antibody significantly blocked the effects of IL-1β on PTC fibronectin secretion (IL-1β, 268.1 ± 30.6 vs. IL-1β ±TGF-β 157.9 ± 14.4%, of control values, P < 0.001) and DNA synthesis (IL-1β 81.0 ± 6.7% vs. IL-1β+αTGF-β 93.4 α± 2.1%, of control values, P < 0.01).

Conclusion
IL-1β acts on human PTC to suppress cell proliferation, enhance fibronectin production and promote α-smooth muscle actin expression. These actions appear to be mediated by a TGF-β1 dependent mechanism and are independent of nitric oxide release.
Keyword Urology & Nephrology
Interstitial Fibrosis
Chronic Kidney Failure
Myofibroblast.
Nitric Oxide Synthase
Transforming Growth Factor-beta
Tumor-necrosis-factor
Human Renal Fibroblasts
Nitric-oxide Production
Tubulointerstitial Fibrosis
Receptor Antagonist
Mesangial Cells
Glomerulonephritis
Myofibroblasts
Transport
Synthase
Transforming Growth Factor β
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
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Created: Wed, 15 Aug 2007, 03:00:49 EST