单侧输尿管梗阻后 P2X4 受体缺陷小鼠的肾纤维化过度。
Exaggerated renal fibrosis in P2X4 receptor-deficient mice following unilateral ureteric obstruction.
机构信息
Imperial College Renal and Transplant Centre, Hammersmith Hospital, Imperial College London, London, UK Clinic for Transplantations immunology and Nephrology, University Hospital Basel, Basel, Switzerland Department of Biomedicine, Molecular Nephrology, University Hospital Basel, Basel, Switzerland.
Imperial College Renal and Transplant Centre, Hammersmith Hospital, Imperial College London, London, UK.
出版信息
Nephrol Dial Transplant. 2014 Jul;29(7):1350-61. doi: 10.1093/ndt/gfu019. Epub 2014 Feb 25.
BACKGROUND
The ATP-sensitive P2X7 receptor (P2X7R) has been shown to contribute to renal injury in nephrotoxic nephritis, a rodent model of acute glomerulonephritis, and in unilateral ureteric obstruction (UUO), a rodent model of chronic interstitial inflammation and fibrosis. Renal tubular cells, endothelial cells and macrophages also express the closely related P2X4 receptor (P2X4R), which is chromosomally co-located with P2X7R and has 40% homology; it is also pro-inflammatory and has been shown to interact with P2X7R to modulate its pro-apoptotic and pro-inflammatory effects. Therefore, we chose to explore the function of P2X4R in the UUO model of renal injury using knockout mice. We hypothesized that UUO-induced tubulointerstitial damage and fibrosis would also be attenuated in P2X4R(-/-) mice.
METHOD
P2X4R(-/-) and wild-type (WT) mice were subjected to either UUO or sham operation. Kidney samples taken on Days 7 and 14 were evaluated for renal inflammation and fibrosis, and expression of pro-fibrotic factors.
RESULTS
To our surprise, the obstructed kidney in P2X4R(-/-) mice showed more severe renal injury, more collagen deposition (picrosirius red staining, increase of 53%; P < 0.05) and more type I collagen staining (increase of 107%; P < 0.01), as well as increased mRNA for TGF-β (increase of 102%, P < 0.0005) and CTGF (increase of 157%; P < 0.05) by Day 14, compared with the UUO WT mice.
CONCLUSION
These findings showed that lack of P2X4R expression leads to increased renal fibrosis, and increased expression of TGF-β and CTGF in the UUO model.
背景
ATP 敏感性 P2X7 受体（P2X7R）已被证明在肾毒性肾炎（一种啮齿动物急性肾小球肾炎模型）和单侧输尿管梗阻（UUO）（一种啮齿动物慢性间质性炎症和纤维化模型）中导致肾损伤。肾小管细胞、内皮细胞和巨噬细胞也表达密切相关的 P2X4 受体（P2X4R），该受体与 P2X7R 染色体位置相邻，具有 40%的同源性；它也具有促炎作用，并已被证明与 P2X7R 相互作用，调节其促凋亡和促炎作用。因此，我们选择使用基因敲除小鼠来探索 P2X4R 在 UUO 模型肾损伤中的功能。我们假设 P2X4R(-/-) 小鼠的 UUO 诱导的肾小管间质损伤和纤维化也会减轻。
方法
P2X4R(-/-)和野生型（WT）小鼠分别接受 UUO 或假手术。在第 7 天和第 14 天采集肾脏样本，评估肾脏炎症和纤维化以及促纤维化因子的表达。
结果
令我们惊讶的是，P2X4R(-/-) 小鼠的梗阻肾脏显示出更严重的肾损伤，更多的胶原沉积（天狼猩红染色，增加 53%；P < 0.05）和更多的 I 型胶原染色（增加 107%；P < 0.01），以及 TGF-β（增加 102%，P < 0.0005）和 CTGF（增加 157%，P < 0.05）的 mRNA 表达在第 14 天也增加。
结论
这些发现表明缺乏 P2X4R 表达导致 UUO 模型中肾纤维化增加，以及 TGF-β和 CTGF 的表达增加。
Zotero 插件