The role of proximal tubular cells in interstitial fibrosis: understanding TGF-beta1.
In PTC, it is clear that TGF-beta1 synthesis may be controlled independently at the levels of transcription and translation. In the context of diabetic nephropathy glucose is a potent stimulus of TGF-beta1 promoter activity. The resultant transcript is however poorly translated such that stimulation of PTC with glucose does not increase de novo TGF-beta1 protein synthesis. Although diabetes is a "metabolic" disease, in the kidney, nephropathy is associated with an inflammatory cell infiltrate. For example using the GK rat model of type II diabetes, we have demonstrated that progressive renal disease is associated with a prominent macrophage influx. This led us to examine TGF-beta1 regulation when the effects of macrophage derived cytokines such as platelet derived growth factor and interleukin-1 are combined with exposure to elevated glucose concentrations. These studies have demonstrated that such cytokines specifically facilitate translation of glucose induced TGF-beta1 transcripts. In addition, direct interaction between monocyte-macrophage CD18 and PTC cell surface ICAM-1 stimulates TGF-beta1 synthesis. Recent data from numerous experimental systems have suggested that the extracellular matrix component hyaluronan (HA) may be involved in the regulation of the inflammatory process. We have now identified HA based structures synthesised on the surface of PTC, which act to prevent PTC-macrophage interaction through ICAM-1 thus preventing macrophage driven TGF-beta1 synthesis. Disease promoting cytokines such as IL-1beta down-regulate these structures whilst potential therapeutic agents such as BMP-7 increase their assembly, that HA may possess disease limiting activity.
Phillips
Aled
A
Institute of Nephrology, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom. PhillipsAO@cf.ac.uk
D000818:Animals; D005355:Fibrosis; D006801:Humans; D006820:Hyaluronic Acid / Q000502:physiology; D007668:Kidney / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D008264:Macrophages / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
D053773:Transforming Growth Factor beta1; D006820:Hyaluronic Acid