NDT Advance Access originally published online on March 15, 2005
Nephrology Dialysis Transplantation 2005 20(5):1013-1014; doi:10.1093/ndt/gfh733
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Differential effects of albumin on cytokine gene expression in proximal tubular epithelial cells
Sir,
Protein-induced activation of proximal tubular epithelial cells (PTECs) plays a central role in mediating interstitial macrophage accumulation in chronic glomerular diseases [1]. In vitro, short-term exposure of cultured PTECs to nephrotic-range concentrations of native or modified (glycated or lipidated) plasma proteins (albumin, IgG and complement) induces the gene expression of chemoattractants (such as RANTES, MCP-1, endothelin and fibronectin) and alters the spatial arrangement of adhesion molecules [1]. This study was undertaken to investigate whether albumin has differential effects on the gene expression of cytokines with classical macrophage activating [interleukin-1ß (IL-1ß), tumour necrosis factor-
(TNF-), IL-6 and IL-12 p40], deactivating (IL-4 and IL-10) or immunomodulatory transforming growth factor-ß (TGF-ß1) properties.
Confluent primary cultured rat PTECs were exposed to vehicle, lipopolysaccharide (5 µg/ml, LPS, Escherichia coli, serotype 026:B6, Sigma-Aldrich, Australia) or endotoxin-free delipidated bovine serum albumin (dBSA, 15 mg/ml, Sigma-Adrich, Australia) for 8 h [2,3]. Isolation of total cellular RNA and mRNA expression was assessed by semi-quantitative reverse transcription–polymerase chain reaction (RT–PCR) as described previously [2,3].
In unstimulated PTECs, weak constitutive expression of all cytokines was detected, except for IL-1ß and IL-4 (Figure 1). Exposure to LPS induced IL-1ß, IL-6, IL-10, IL-12 p40 and TNF-. In contrast, dBSA increased IL-1ß, TNF- and IL-6, but did not induce IL-10 or IL-12 p40. For both LPS and dBSA, there was a trend for an increase in TGF-ß1 mRNA, and IL-4 remained undetectable.
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These results demonstrate that albumin is proinflammatory and selectively induced the transcription of cytokines with classical macrophage-activating properties in PTECs. The mechanism by which albumin mediates these proinflammatory effects requires evaluation of the signal transducing pathways, and it remains to be determined whether other plasma proteins share these effects. In contrast to human PTECs [4], TGF-ß1 mRNA was not significantly induced in rat PTECs by albumin, and this might be due to differences in the duration of albumin exposure (24 h in [4]) and/or possibly species-specific variations.
Centre for Transplant and Renal Research Westmead Millennium Institute The University of Sydney at Westmead Hospital Westmead Sydney Australia 2145 Email: g.rangan{at}wmi.usyd.edu.au
Acknowledgments
This study was supported by the Australian Kidney Foundation (G.K.R.) and project grant 970721 from the National Health Medical Research Council of Australia (D.C.H.).
Conflict of interest statement. None declared.
References
- Zoja C, Benigni A, Remuzzi G. Cellular responses to protein overload: key event in renal disease progression. Curr Opin Nephrol Hypertens 2004; 13: 31–37[Web of Science][Medline]
- Wang Y, Chen J, Chen L, Tay YC, Rangan GK, Harris DC. Induction of monocyte chemoattractant protein-1 in proximal tubule cells by urinary protein. J Am Soc Nephrol 1997; 8: 1537–1545[Abstract]
- Rangan GK, Wang Y, Tay YC, Harris DC. Inhibition of NF-
B with antioxidants is correlated with reduced cytokine transcription in PTC. Am J Physiol 1997; 277: F779–F789
- Yard BA, Chorianopoulos E, Herr D, van der Woude FJ. Regulation of endothelin and transforming growth factor-ß1 production in cultured proximal tubular cells by albumin and heparan sulphate glycosaminoglycans. Nephrol Dial Transplant 2001; 16: 1769–1775
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