Abstract
Patients with end-stage kidney disease on peritoneal dialysis often develop progressive scarring of the peritoneal tissues. This manifests as submesothelial thickening and is associated with increased vascularization that leads to ultrafiltration dysfunction. Hypoxia induces a characteristic series of responses including angiogenesis and fibrosis. We investigated the role of hypoxia in peritoneal membrane damage. An adenovirus expressing transforming growth factor (TGF) β was used to induce peritoneal fibrosis. We evaluated the effect of the mTOR inhibitor rapamycin, which has been previously shown to block hypoxia-inducible factor (HIF) 1α. We also assessed the effect of HIF1α independently using an adenovirus expressing active HIF1α. To identify the TGFβ1-independent effects of HIF1α, we expressed HIF1α in the peritoneum of mice lacking the TGFβ signalling molecule Smad3. We demonstrate that TGFβ-induced fibroproliferative tissue is hypoxic. Rapamycin did not affect the early angiogenic response, but inhibited angiogenesis and submesothelial thickening 21 days after induction of fibrosis. In primary mesothelial cell culture, rapamycin had no effect on TGFβ-induced vascular endothelial growth factor (VEGF) but did suppress hypoxia-induced VEGF. HIF1α induced submesothelial thickening and angiogenesis in peritoneal tissue. The fibrogenic effects of HIF1α were Smad3 dependent. In summary, submesothelial hypoxia may be an important secondary factor, which augments TGFβ-induced peritoneal injury. The hypoxic response is mediated partly through HIF1α and the mTOR inhibitor rapamycin blocks the hypoxic-induced angiogenic effects but does not affect the direct TGFβ-mediated fibrosis and angiogenesis.
Highlights
The peritoneal membrane provides life support for patients who rely on peritoneal dialysis (PD) as their renal replacement therapy
We have demonstrated that adenovirus-mediated gene transfer of transforming growth factor (TGF) to the peritoneum results in functional and structural changes similar to those seen in patients on long-term PD [10]
Peritoneal fibrosis and angiogenesis have been demonstrated to be associated with epithelialto-mesenchymal transition (EMT) of mesothelial cells [11] and we have shown that TGF induces a pattern of EMT similar to that which is seen in the peritoneal tissues of PD patients [12]
Summary
The peritoneal membrane provides life support for patients who rely on peritoneal dialysis (PD) as their renal replacement therapy. Vol 16, No 8, 2012 demonstrated an association between peritoneal effluent TGF concentration and peritoneal membrane injury in patients on PD therapy [7,8,9]. We have demonstrated that adenovirus-mediated gene transfer of TGF to the peritoneum results in functional and structural changes similar to those seen in patients on long-term PD [10]. Peritoneal fibrosis and angiogenesis have been demonstrated to be associated with epithelialto-mesenchymal transition (EMT) of mesothelial cells [11] and we have shown that TGF induces a pattern of EMT similar to that which is seen in the peritoneal tissues of PD patients [12]
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