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Myricanol represses renal fibrosis by activating tubular TFAM-ZNRF1/LCN2 pathway to improve mitochondrial bioenergetics
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  • Ming Zheng,
  • Jun You,
  • Zheng Hu,
  • Bao Gao,
  • Wei Cui,
  • Wan Yao,
  • Qiao Jiang,
  • Feng Su,
  • Xue Sun,
  • Lei La
Ming Zheng
Southern Medical University Nanfang Hospital
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Jun You
Southern Medical University
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Zheng Hu
Southern Medical University Nanfang Hospital
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Bao Gao
Southern Medical University
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Wei Cui
Southern Medical University First Affiliated Hospital
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Wan Yao
Southern Medical University
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Qiao Jiang
Southern Medical University Nanfang Hospital
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Feng Su
Southern Medical University Nanfang Hospital
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Xue Sun
Southern Medical University
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Lei La
Southern Medical University Nanfang Hospital

Corresponding Author:[email protected]

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Abstract

Background: Mitochondrial biology destroy lead to renal fibrosis. Targeted therapy of ferroptosis may play an important role in protecting renal functions. Myricanol has been shown ameliorate muscle dysfunction by increasing mitochondrial biogenesis. However, few studies on myricanol in renal fibrosis has been performed. Purpose: We explore that myricanol can relieve renal fibrosis by improving mitochondrial bioenergy and inhibiting ferroptosis. Approach: Renal ferroptosis model was established using bilateral ischemia reperfusion (BIRI), which was used to study association between ferroptosis and renal fibrosis. Ferroptosis associated protein including zinc and ring finger 1 (ZNRF1) and iron transport-related protein lipocalin-2 (LCN2) interactions were verified by co-immunoprecipitation. Two concentrations of myricanol, namely 0.5 mg/kg and 2 mg/kg, were included to treat unilateral ureteral obstruction (UUO) induced mouse model of chronic kidney disease (CKD). Results: We have shown that myricanol could inhibits ferroptosis, maintains mitochondrial integrity and renal function. Mitochondrial copy number were decreased in CKD patient blood sample. We further confirmed that primary renal tubular cells with TFAM deficiency were more prone to ferroptosis. Transcriptional sequencing showed the level of ZNRF1 having significant differences between TFAM-/- and TFAM+/+ group. TFAM deficiency decrease the interaction between LCN2 and ZNRF1. Treatment with myricanol reduced renal fibrosis by regulating TFAM expression and ferroptosis. Conclusions: Our study firstly demonstrated that myricanol strengthen tubular bioenergetic capacity depended on TFAM increasing the interaction between LCN2 and ZNRF1 to inhibit ferroptosis and suggested that myricanol might be promising drugs for treating renal fibrosis.