Juan Chen, Lili Fu, Mengjin Li, Kun Xie, Xinming Li, Xu-Jie Zhou, Li Yang, Liming Zhang, Cheng Xue, Zhiguo Mao
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引用次数: 0
Abstract
Background: 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.
Methods: 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.
Results: Meta-analysis confirmed significantly reduced circulating BDNF in CKD patients (WMD = -0.62 ng/mL, 95% CI [-0.98, -0.25], P < 0.001; I2 = 87%). In 14-day UUO mice, renal immunohistochemistry (IHC) showed significantly reduced BDNF expression (P < 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 Bdnf levels were lower in renal proximal tubule (PT) cells, macrophages (Mφ), and podocytes in UUO mice compared to normal controls, Additionally, Bdnf-as-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 Bdnf-as expression at days 14 and 18 post-obstruction.
Conclusion: 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 Bdnf-as.
期刊介绍：
Much of contemporary investigation in the life sciences is devoted to the molecular-scale understanding of the relationships between genes and the environment — in particular, dynamic alterations in the levels, modifications, and interactions of cellular effectors, including proteins. Frontiers in Molecular Biosciences offers an international publication platform for basic as well as applied research; we encourage contributions spanning both established and emerging areas of biology. To this end, the journal draws from empirical disciplines such as structural biology, enzymology, biochemistry, and biophysics, capitalizing as well on the technological advancements that have enabled metabolomics and proteomics measurements in massively parallel throughput, and the development of robust and innovative computational biology strategies. We also recognize influences from medicine and technology, welcoming studies in molecular genetics, molecular diagnostics and therapeutics, and nanotechnology.
Our ultimate objective is the comprehensive illustration of the molecular mechanisms regulating proteins, nucleic acids, carbohydrates, lipids, and small metabolites in organisms across all branches of life.
In addition to interesting new findings, techniques, and applications, Frontiers in Molecular Biosciences will consider new testable hypotheses to inspire different perspectives and stimulate scientific dialogue. The integration of in silico, in vitro, and in vivo approaches will benefit endeavors across all domains of the life sciences.
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