FXR作为急性肾损伤潜在治疗靶点的作用及机制研究

Acute kidney injury (AKI),which is characterized by necrosis of tubular epithelial cells，is one of the common complications in clinical practice and has high incidence and mortality. The treatment of AKI is still limited. Farnesoid X receptor (FXR) is bile acid receptor.Recent studies demonstrated that FXR helped liver regeneration in response to increased bile acid stress after 70% hepatectomy and FXR agonist could inhibit serum deprivation-induced liver cell apoptosis. Our priliminary data showed that FXR was highly expressed in renal tubular epithelial cells and decreased while ischemic/reperfusion induced AKI. FXR agonist could upregulate Sirt1 expression and Sirt1 could protect renal epithelial cell from injuries. So we suppose that FXR can prevent renal tubular epithelial cells from ischemic/reperfusion induced injury by upregulating the expression of Sirt1. To examine this hypothesis, we will use FXR agonist and FXR knockout mice and then establish ischemic/reperfusion animal models. We will further explore the mechanisms of FXR upregulating the expression of Sirt1. This study has significant value in understanding the role of FXR in kidney and the mechanism of AKI. More importantly, the study maybe tell us a new therapeutic target of AKI.

急性肾损伤（AKI）是以肾小管上皮细胞损伤、坏死为显著特点的一类疾病，发病率和死亡率均高，寻找预防或治疗AKI的有效措施是肾脏病领域研究的热点。FXR又称胆汁酸受体，在肝脏具有抑制凋亡、促进再生的作用。我们前期研究表明，FXR在肾小管上皮细胞中呈高表达，缺血再灌注损伤后FXR表达减少，FXR可上调Sirt1表达，而Sirt1又具有抑制肾小管上皮细胞凋亡，促进肾小管再生的作用。因此，我们推测FXR可能可以通过上调Sirt1表达保护肾小管上皮细胞，减轻AKI的严重程度。本研究拟采用FXR激动剂及FXR基因缺陷的小鼠，构建双肾缺血再灌注损伤模型，判断FXR是否能通过上调Sirt1表达起到保护肾功能，减轻AKI严重程度的作用，并将进一步探讨FXR上调Sirt1表达的机制。该研究对认识FXR在肾脏中的作用以及AKI的发病机制具有重要的意义，更重要的是该研究对探寻AKI新的治疗靶点具有重要的价值。

急性肾损伤（AKI）是以肾小管上皮细胞损伤、坏死为显著特点的一类疾病，发病率和死亡率均高，寻找预防或治疗AKI的有效措施是肾脏病领域研究的热点。FXR又称胆汁酸受体，在肝脏具有抑制凋亡、促进再生的作用。本课题研究发现FXR选择性高表达于近端肾小管上皮细胞的细胞核中；缺血再灌注损伤后FXR表达明显减少，并可在肾小管上皮细胞修复后恢复表达；FXR基因缺陷加重缺血再灌注诱导的AKI的严重程度，降低AKI的生存率；体外研究发现过氧化氢刺激可促进FXR，Sirt1及E2F1表达；采用FXR激动剂可上调Sirt1表达，减轻过氧化氢所致肾小管上皮细胞的凋亡，抑制Sirt1表达可阻断FXR对肾小管上皮细胞的保护作用；此外，FXR激动剂也可上调E2F1的表达，抑制E2F1也可阻断FXR对肾小管上皮细胞的保护作用，但是抑制E2F1并未阻断FXR对Sirt1表达的上调作用。目前已存在FXR的激动剂，该研究不仅对认识AKI的发病机制及FXR在AKI中的作用有重要意义，对于AKI的治疗也具有重要的价值。