Chen Juan, Fu Lili, Li Mengjin, Xie Kun, Li Xinming, Zhou Xu-Jie, Yang Li, Zhang Liming, Xue Cheng, Mao Zhiguo
Department of Nephrology, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, Second Military Medical University, Shanghai, China.
Department of Nephrology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China.
Front Mol Biosci. 2025 Jul 28;12:1627534. doi: 10.3389/fmolb.2025.1627534. eCollection 2025.
Chronic kidney disease (CKD) is a progressive disorder characterized by declining renal function and systemic metabolic disturbances. Brain-derived neurotrophic factor (BDNF), a key member of the neurotrophic family, plays critical roles in neuronal function and muscular metabolism. However, the evidence and regulatory mechanisms underlying decreased BDNF levels in CKD remain inconclusive.
This study systematically evaluated circulating BDNF alterations in CKD patients through a meta-analysis of clinical studies involving 1,549 participants, complemented by experimental validation in unilateral ureteral obstruction (UUO) mice and single-cell transcriptomic database analysis to investigate tissue-specific BDNF protein expression and regulatory patterns.
Meta-analysis confirmed significantly reduced circulating BDNF in CKD patients (WMD = -0.62 ng/mL, 95% CI [-0.98, -0.25], < 0.001; = 87%). In 14-day UUO mice, renal immunohistochemistry (IHC) showed significantly reduced BDNF expression ( < 0.001), which was further validated by Western blot analysis demonstrating a progressive decline in BDNF protein levels from day 14 to day 21 post-obstruction. Single-cell mRNA sequencing further confirmed that levels were lower in renal proximal tubule (PT) cells, macrophages (Mφ), and podocytes in UUO mice compared to normal controls, Additionally, -a long non-coding RNA known to epigenetically repress BDNF-was significantly upregulated in proximal tubules of CKD patients based on human transcriptomic data. This upregulation was validated in UUO mice by qPCR, showing a time-dependent increase in expression at days 14 and 18 post-obstruction.
This study integrated meta-analysis, murine model validation, and single-cell transcriptomic profiling to demonstrate a significant reduction of BDNF in CKD. Furthermore, renal BDNF expression decreased locally, predominantly originating from proximal tubule cells, macrophages, and podocytes, possibly epigenetically inhibited by the upregulation of lnc RNA .
慢性肾脏病（CKD）是一种以肾功能下降和全身代谢紊乱为特征的进行性疾病。脑源性神经营养因子（BDNF）是神经营养因子家族的关键成员，在神经元功能和肌肉代谢中起关键作用。然而，CKD中BDNF水平降低的证据和调节机制仍不明确。
本研究通过对涉及1549名参与者的临床研究进行荟萃分析，系统评估了CKD患者循环中BDNF的变化，并通过单侧输尿管梗阻（UUO）小鼠实验验证和单细胞转录组数据库分析，以研究组织特异性BDNF蛋白表达和调节模式。
荟萃分析证实CKD患者循环中BDNF显著降低（加权平均差=-0.62 ng/mL，95%置信区间[-0.98，-0.25]，P<0.001；I²=87%）。在14天的UUO小鼠中，肾脏免疫组织化学（IHC）显示BDNF表达显著降低（P<0.001），蛋白质印迹分析进一步证实，梗阻后第14天至第21天BDNF蛋白水平逐渐下降。单细胞mRNA测序进一步证实，与正常对照相比，UUO小鼠肾近端小管（PT）细胞、巨噬细胞（Mφ）和足细胞中的BDNF水平较低。此外，根据人类转录组数据，已知可通过表观遗传抑制BDNF的长链非编码RNA——lncRNA在CKD患者近端小管中显著上调。qPCR在UUO小鼠中验证了这种上调，显示梗阻后第14天和第18天lncRNA表达呈时间依赖性增加。
本研究综合荟萃分析、小鼠模型验证和单细胞转录组分析，证明CKD中BDNF显著降低。此外，肾脏BDNF表达在局部降低，主要源于近端小管细胞、巨噬细胞和足细胞，可能受到lncRNA上调的表观遗传抑制。
