期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 319, 期 2, 页码 F202-F214出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00132.2020
关键词
lipid metabolism; microRNA; peroxisome proliferator-activated receptor-alpha; renal injury
资金
- National Natural Science Foundation of China [8170101445]
- Beijing Municipal Science and Technology Commission [7182191]
- Capital Health Research and Development of Special [2016-2-2242]
Kidney stone disease is a crystal concretion formed in the kidneys that has been associated with an increased risk of chronic kidney disease. MicroRNAs are functionally involved in kidney injury. Data mining using a microRNA array database suggested that miR-21 may be associated with calcium oxalate monohydrate (COM)-induced renal tubular cell injury. Here, we confirmed that COM exposure significantly upregulated miR-21 expression, inhibited proliferation, promoted apoptosis, and caused lipid accumulation in an immortalized renal tubular cell line (HK-2). Moreover, inhibition of miR-21 enhanced proliferation and decreased apoptosis and lipid accumulation in HK-2 cells upon COM exposure. In a glyoxylate-induced mouse model of renal calcium oxalate deposition. increased miR-21 expression, lipid accumulation, and kidney injury were also observed. In silica analysis and subsequent experimental validation confirmed the peroxisome proliferator-activated receptor (PPAR)-alpha gene (PPARA) a key gene in fatty acid oxidation, as a direct miR-21 target. Suppression of miR-21 by miRNA antagomiR or activation of PPAR-alpha by its selective agonist fenofibrate significantly reduced renal lipid accumulation and protected against renal injury in vivo. In addition. miR-21 was significantly increased in urine samples from patients with calcium oxalate renal stones compared with healthy volunteers. In situ hybridization of biopsy samples from patients with nephrocalcinosis revealed that miR-21 was also significantly upregulated compared with normal kidney tissues from patients with renal cell carcinoma who underwent radical nephrectomy. These results suggested that miR-21 promoted calcium oxalate-induced renal tubular cell injury by targeting PPARA, indicating that miR-21 could be a potential therapeutic target and biomarker for nephrolithiasis.
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