干细胞因子调控细胞自噬对肾小管上皮细胞衰老的影响

Renal tubules have the significant effects on maintaining the water-salt balance. The aging of tubular epithelial cells (TECs) increases the risk of renal tubular diseases. However, limited mechanisms of TEC aging are revealed. Autophagy is an important mechanism of cell aging. Under the influence of calorie restriction and oxidative stress, PI3K/mTOR pathway is inhibited leading to the activation of autophagy and delaying the cell aging. According to our previous study, with the age increasing, the glomerular filtration rate was decreasing, but the level of serum stem cell factor (SCF) was increasing. The level of SCF was negatively correlated with kidney function, which may indicate the specific relationship between SCF and kidney aging. SCF mainly distributed on TECs in kidney, and participated in various kidney diseases, such as acute kidney injury, interstitial nephritis and so on. Thus, we infer that SCF may activate PI3K/mTOR pathway, inhibit autophagy and accelerate the TEC aging. In this study, we intend to regulate the expression of SCF in cells and animal models. Then we would compare the activation of PI3K/mTOR pathway, autophagy and aging degrees of TECs. We aim at investigating the possible mechanism of SCF in TEC aging. This study will find new biomarkers and intervention targets of kidney aging.

肾小管在维持机体水电解质平衡中发挥重要作用，肾小管上皮细胞（TEC）衰老增加了肾小管疾病的风险，但目前对于TEC衰老机制尚不清楚。自噬是导致细胞衰老的重要机制，限食和氧化应激均可激活PI3K/mTOR通路，增强细胞自噬、延缓细胞衰老。我们前期研究发现，随年龄增加肾小球滤过率逐年下降，而血清干细胞因子（SCF）浓度逐年上升，二者呈负相关，则SCF可能参与肾脏衰老机制。SCF在肾脏中主要分布于TEC，参与急性肾脏损伤、间质性肾炎等多种疾病发生。因此，我们推测TEC上的SCF可通过激活PI3K/mTOR通路抑制细胞自噬以加速TEC衰老。本研究中，我们拟在组织、细胞和动物水平改变SCF表达，检测PI3K/mTOR通路活性、自噬及TEC衰老程度，以探究TEC衰老过程中SCF的作用机制。此研究对于揭示TEC衰老机制，探寻延缓TEC衰老的药物干预新靶点具有重要意义。

肾小管在维持机体水电解质平衡中发挥重要作用，肾小管上皮细胞（TEC）衰老增加了肾小管疾病的风险，但目前对于TEC衰老机制尚不清楚。自噬是导致细胞衰老的重要机制，我们在组织、细胞和动物水平改变SCF表达，检测PI3K/mTOR通路活性、自噬及肾脏衰老程度，以探究肾脏衰老过程中SCF的作用机制。我们的研究发现，在慢性肾衰竭小鼠模型中，肾组织SCF表达增高，且SCF主要分布在TEC表面；细胞学实验证实衰老TEC中，SCF可激活PI3K/mTOR通路，上调LC3 II/I表达、下调P62表达，抑制自噬溶酶体降解进而阻断细胞自噬流，促进TEC衰老。此研究对于揭示肾脏衰老机制，探寻延缓肾脏衰老的药物干预新靶点具有重要意义。