MiR-21 promotes calcium oxalate-induced renal tubular cell injury by targeting PPARA.

Abstract

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 silico analysis and subsequent experimental validation confirmed the peroxisome proliferator-activated receptor (PPAR)-α 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-α 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.

• Authors: Boxing Su, Haibo Han, Chaoyue Ji, Weiguo Hu, Jingjing Yao, Jianghui Yang, Yunfei Fan, Jianxing Li
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 319 Issue 2 Pg. F202-F214 (08 01 2020) ISSN: 1522-1466 [Electronic] United States
• PMID: 32628541 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• MIRN21 microRNA, human
• MicroRNAs
• PPAR alpha
• PPARA protein, human
• Calcium Oxalate

Topics

• Apoptosis (drug effects, genetics)
• Biomarkers (metabolism)
• Calcium Oxalate (metabolism, pharmacology)
• Epithelial Cells (drug effects, metabolism)
• Humans
• Kidney (injuries, metabolism)
• Kidney Calculi (pathology)
• Kidney Tubules (drug effects, metabolism)
• MicroRNAs (genetics, pharmacology)
• Nephrocalcinosis (metabolism)
• PPAR alpha (drug effects)
• Signal Transduction (drug effects)