血红素氧合酶-1对肾间质纤维化的作用和机制研究

Tubule interstitial fibrosis is final common pathways to end-stage renal disease and strongly associated with inflammation and loss of peritubular capillary．But effective therapeutic strategy is limited. Many studies have demonstrated that heme oxygenase-1 (HO-1) involved in diverse biological processes as a cytoprotective molecule, including antiinflammatory, antioxidant, antiapoptotic, antiproliferative, and immunomodulatory effects. However, the role of HO-1 in reversing renal fibrosis has not yet been addressed. Our recent studies have demonstrated that macrophages are increasingly recognized as a major innate immune cell that have the capacity to regulate both fibrosis and repair of the kidney by Wnt sinaling. New evidence has confirmed that pericytes and perivascular fibroblasts were the major source of myofibroblasts which play major roles in fibrosis. Blockade of pericyte-endothelial cross-talk in response to renal injury prevents both microvascular rarefaction and interstitial fibrosis. In the present study, we investagte whether HO-1 inhibits tubule interstitial fibrosis using HO-1 transgenic mouse and also explored the potential mechanisms focused on macrophage wnt signaling, pericyte myofibroblast transdifferentiation and pericyte-endothelial cross-talk. We aim to develope new therapeutic stragety for kidney fibrosis.

肾间质纤维化是肾脏病进展致终末期肾衰的共同通路,与炎性细胞浸润及管周毛细血管丢失密切相关，但至今缺乏有效治疗措施。大量研究证明血红素氧合酶1（HO-1）有抗炎、抗氧化、抗凋亡、抗增殖和免疫调节作用，且有明显血管保护作用，但在肾间质纤维化中的作用尚不清楚。我们前期研究证实巨噬细胞通过Wnt 信号通路在肾脏疾病发生发展中起双重作用，既促进肾脏修复，又导致肾纤维化。新研究证实血管周细胞和成纤维细胞是肌成纤维细胞(在纤维化中起主要作用)的主要来源，调控肾损伤中周细胞和内皮细胞之间的crosstalk，减少周细胞增殖分化和管周毛细血管丢失，可阻止肾间质纤维化。本研究用野生鼠和HO-1高表达转基因小鼠制作肾纤维化模型，从巨噬细胞Wnt信号通路及周细胞向肌成纤维细胞转分化和内皮细胞间的crosstalk入手，研究HO-1对肾间质纤维化的影响，阐明其作用机制，为肾间质纤维化的治疗提供新的理论依据和干预措施

肾纤维化在慢性肾脏病的发生发展中起到重要作用，许多研究已经证明：血红素氧合酶1（HO-1）作为细胞保护因子，具有抗炎、抗氧化、抗凋亡、抗增殖和免疫调节剂的作用。然而，HO-1抑制肾间质纤维化的作用及机制尚不清楚。本研究中，我们选择HO-1转基因(TG)小鼠为实验对象，制作单侧输尿管梗阻模型，我们发现无论是在TG小鼠还是在野生（WT）小鼠的UUO模型肾脏内HO-1都反应性高表达。在对照组，同WT小鼠相比TG小鼠肾脏HO-1mRNA及蛋白表达增加，在UUO模型之后，HO-1的表达进一步升高，并在整个实验过程中始终保持高水平。在研究中我们发现，HO-1的高表达抑制了小鼠肾脏管周毛细血管丢失，抑制了成纤维细胞的活化和增殖，抑制了肾小管间质巨噬细胞浸润，并调节了炎症因子的释放。我们同时发现：HO-1高表达抑制了 Wnt/β-catenin信号通路的活化。因此，上述数据表明，HO-1可能通过调节炎症反应和抑制 Wnt/β-catenin信号通路来抑制肾间质纤维化，为今后治疗肾间质纤维化提供新的思路。