Yanai Katsunori, Kaneko Shohei, Ishii Hiroki, Aomatsu Akinori, Hirai Keiji, Ookawara Susumu, Morishita Yoshiyuki
Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
Division of Intensive Care Unit, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
Front Med (Lausanne). 2022 May 13;9:849075. doi: 10.3389/fmed.2022.849075. eCollection 2022.
Age-dependent renal impairment contributes to renal dysfunction in both the general population and young and middle-aged patients with renal diseases. Pathological changes in age-dependent renal impairment include glomerulosclerosis and tubulointerstitial fibrosis. The molecules involved in age-dependent renal impairment are not fully elucidated. MicroRNA (miRNA) species were reported to modulate various renal diseases, but the miRNA species involved in age-dependent renal impairment are unclear. Here, we investigated miRNAs in age-dependent renal impairment, and we evaluated their potential as biomarkers and therapeutic targets.
We conducted an initial microarray profiling analysis to screen miRNAs whose expression levels changed in kidneys of senescence-accelerated resistant (SAMR1)-10-week-old (wk) mice and SAMR1-50wk mice and senescence-accelerated prone (SAMP1)-10wk mice and SAMP1-50wk mice. We then evaluated the expressions of differentially expressed miRNAs in serum from 13 older patients (>65 years old) with age-dependent renal impairment (estimated glomerular filtration ratio <60 mL/min/1.73 m) by a quantitative real-time polymerase chain reaction (qRT-PCR) and compared the expressions with those of age-matched subjects with normal renal function. We also administered miRNA mimics or inhibitors (5 nmol) with a non-viral vector (polyethylenimine nanoparticles: PEI-NPs) to SAMP1-20wk mice to investigate the therapeutic effects.
The qRT-PCR revealed a specific miRNA (miRNA-503-5p) whose level was significantly changed in SAMP1-50wk mouse kidneys in comparison to the controls. The expression level of miRNA-503-5p was upregulated in the serum of the 13 patients with age-dependent renal impairment compared to the age-matched subjects with normal renal function. The administration of a miRNA-503-5p-inhibitor with PEI-NPs decreased the miRNA-503-5p expression levels, resulting in the inhibition of renal fibrosis in mice via an inhibition of a pro-fibrotic signaling pathway and a suppression of glomerulosclerosis in mice by inhibiting intrinsic signaling pathways.
The serum levels of miRNA-503-5p were decreased in patients with age-dependent renal impairment. However, inhibition of miRNA-503-5p had no effect on age-dependent renal impairment, although inhibition of miRNA-503-5p had therapeutic effects on renal fibrosis and glomerulosclerosis in an animal model. These results indicate that miRNA-503-5p might be related to age-dependent renal impairment.
年龄相关性肾功能损害在普通人群以及中青年肾病患者中均会导致肾功能障碍。年龄相关性肾功能损害的病理变化包括肾小球硬化和肾小管间质纤维化。参与年龄相关性肾功能损害的分子尚未完全阐明。据报道，微小RNA（miRNA）可调节多种肾脏疾病，但参与年龄相关性肾功能损害的miRNA种类尚不清楚。在此，我们研究了年龄相关性肾功能损害中的miRNA，并评估了它们作为生物标志物和治疗靶点的潜力。
我们进行了初步的微阵列分析，以筛选在快速老化抗性（SAMR1）-10周龄（wk）小鼠和SAMR1-50wk小鼠以及快速老化易感性（SAMP1）-10wk小鼠和SAMP1-50wk小鼠肾脏中表达水平发生变化的miRNA。然后，我们通过定量实时聚合酶链反应（qRT-PCR）评估了13例年龄相关性肾功能损害（估计肾小球滤过率<60 mL/min/1.73 m²）的老年患者（>65岁）血清中差异表达miRNA的表达，并将其与年龄匹配的肾功能正常受试者的表达进行比较。我们还将miRNA模拟物或抑制剂（5 nmol）与非病毒载体（聚乙烯亚胺纳米颗粒：PEI-NPs）一起给予SAMP1-20wk小鼠，以研究其治疗效果。
qRT-PCR显示一种特定的miRNA（miRNA-503-5p），与对照组相比，其在SAMP1-50wk小鼠肾脏中的水平有显著变化。与年龄匹配的肾功能正常受试者相比，13例年龄相关性肾功能损害患者血清中miRNA-503-5p的表达水平上调。将miRNA-503-5p抑制剂与PEI-NPs一起给药可降低miRNA-503-5p的表达水平，从而通过抑制促纤维化信号通路抑制小鼠肾纤维化，并通过抑制内在信号通路抑制小鼠肾小球硬化。
年龄相关性肾功能损害患者血清中miRNA-503-5p水平降低。然而，抑制miRNA-503-5p对年龄相关性肾功能损害没有影响，尽管在动物模型中抑制miRNA-503-5p对肾纤维化和肾小球硬化有治疗作用。这些结果表明，miRNA-503-5p可能与年龄相关性肾功能损害有关。
