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Transforming growth factor-₁ differentially mediates fibronectin and inflammatory cytokine expression in kidney tubular cells

¹Department of Medicine, Kolling Institute, University of Sydney, Royal North Shore Hospital, Sydney; ²Department of Medicine, University of Sydney, and Royal Prince Alfred Hospital, Sydney; ³Department of Medicine, St. Vincent’s Hospital, Melbourne, Australia; and ⁴Department of Medicine, University of Toronto, St. Michael’s Hospital, Toronto, Ontario, Canada

Submitted 17 January 2006 ; accepted in final form 15 May 2006

Transforming growth factor-₁ (TGF-₁) is not only an important fibrogenic but also immunomodulatory cytokine in the human kidney. We have recently demonstrated that TGF-₁ induces interleukin-8 (IL-8), macrophage chemoattractant protein-1 (MCP-1), and fibronectin production in renal proximal tubular (HK-2) cells. However, the unique dependence of IL-8, MCP-1, and fibronectin on TGF-₁ expression is unknown. The TGF-₁ gene was effectively silenced in HK-2 cells using small-interference (si) RNA. Basal secretion of IL-8 and MCP-1 decreased (both P < 0.05) but, paradoxically, fibronectin increased (P < 0.05) in TGF-₁-silenced cells compared with cells transfected with nonspecific siRNA. Significant increases were observed in mRNA for the TGF-₂ (P < 0.05), TGF-₃ (P < 0.05) isoforms and pSmad2 (P < 0.05), which were reflected in protein expression. Concurrent exposure to pan-specific TGF- antibody reversed the observed increase in fibronectin expression, suggesting that TGF-₂ and TGF-₃ isoforms mediate the increased fibronectin expression in TGF-₁-silenced cells. An increase in the DNA binding activity of activator protein-1 (AP-1; P < 0.05) was also observed in TGF-₁-silenced cells. In contrast, nuclear factor-B (NF-B) DNA binding activity was significantly decreased (P < 0.0005). These studies demonstrate that TGF-₁ is a key regulator of IL-8 and MCP-1, whereas fibronectin expression is regulated by a complex interaction between the TGF- isoforms in the HK-2 proximal tubular cell line. Decreased expression of TGF-₁ reduces chemokine production in association with reduced NF-B DNA binding activity, suggesting that immunomodulatory pathways in the kidney are specifically dependent on TGF-₁. Conversely, decreased expression of TGF-₁ results in increased TGF-₂, TGF-₃, AP-1, and pSmad2 that potentially mediates the observed increase in fibronectin.

small interference RNA; chemokine; pSmad; activator protein-1; nuclear factor-B

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				W. Qi, X. Chen, Y. Zhang, J. Holian, E. Mreich, R. E. Gilbert, D. J. Kelly, and C. A. Pollock High glucose induces macrophage inflammatory protein-3{alpha} in renal proximal tubule cells via a transforming growth factor-{beta}1 dependent mechanism Nephrol. Dial. Transplant., November 1, 2007; 22(11): 3147 - 3153. [Abstract] [Full Text] [PDF]