Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing, China,
Department of Nephrology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Gerontology. 2024;70(11):1161-1170. doi: 10.1159/000540839. Epub 2024 Aug 13.
Renal interstitial fibrosis is an important pathological basis for kidney ageing and the progression of ageing nephropathy. In the present research, we established an aged mouse model of faecal microbiota transplantation (FMT), identified the rejuvenation features of the kidney in aged male mice, and preliminarily analysed the possible mechanism by which the rejuvenation of the intestinal microbiota reduces renal interstitial fibrosis and delays senescence in aged male mice.
We established an aged male mice model that was treated with FMT (FMT-Old) and a normal aged male mice control group (Old). Differentially expressed cytokines were identified using a cytokine array, and changes in protein expression related to signal transduction pathways in renal tissues were detected using a signalling pathway array. Senescence-associated β-galactosidase and Masson staining were performed to observe the degrees of renal senescence and tubule interstitial fibrosis. Immunohistochemistry was utilized to detect changes in the expression of the ageing markers p53 and p21 and the inflammation-related protein nuclear factor (NF-κB) subunit (RelA/p65).
The pathological features of renal senescence in the FMT-Old group were significantly alleviated, and the levels of the ageing indicators p53 and p21 were decreased (p < 0.05). Ingenuity Pathway Analysis revealed that six differentially expressed cytokines, MIP-3β (CCL-19), E-selectin (SELE), Fas ligand (Fas L/FASLG), CXCL-11 (I-TAC), CXCL-1 and CCL-3 (MIP-1α) were related to a common upstream regulatory protein, RelA/p65, and the expression of this protein was significantly different between groups according to the signalling pathway array.
Our findings suggest that the intestinal microbiota regulates the renal microenvironment by reducing immune inflammatory responses through the inhibition of the NF-κB signalling pathway, thereby delaying renal senescence in aged male mice.
肾间质纤维化是肾脏衰老和衰老性肾病进展的重要病理基础。本研究构建了粪菌移植（FMT）老年雄性小鼠模型，鉴定了老年雄性小鼠肾脏年轻化特征，并初步分析了肠道菌群年轻化减轻老年雄性小鼠肾间质纤维化和延缓衰老的可能机制。
构建 FMT 处理的老年雄性小鼠模型（FMT-Old）和正常老年雄性小鼠对照组（Old）。采用细胞因子芯片鉴定差异表达细胞因子，采用信号通路芯片检测肾组织中与信号转导通路相关的蛋白表达变化。衰老相关β-半乳糖苷酶和 Masson 染色观察肾脏衰老和肾小管间质纤维化程度。免疫组化检测衰老标志物 p53 和 p21 以及炎症相关蛋白核因子（NF-κB）亚基（RelA/p65）的表达变化。
FMT-Old 组肾脏衰老的病理特征明显减轻，衰老标志物 p53 和 p21 的水平降低（p<0.05）。通路分析显示，MIP-3β（CCL-19）、E-选择素（SELE）、Fas 配体（Fas L/FASLG）、CXCL-11（I-TAC）、CXCL-1 和 CCL-3（MIP-1α）这 6 种差异表达细胞因子与共同的上游调节蛋白 RelA/p65 相关，信号通路芯片显示该蛋白在组间的表达存在显著差异。
本研究结果提示，肠道菌群通过抑制 NF-κB 信号通路减少免疫炎症反应来调节肾脏微环境，从而延缓老年雄性小鼠的肾脏衰老。
