Emodin prevents renal ischemia-reperfusion injury via suppression of CAMKII/DRP1-mediated mitochondrial fission.

Abstract

Acute kidney injury (AKI) is a serious threat to human health. Clinically, ischemia-reperfusion (I/R) injury is considered one of the most common contributors to AKI. Emodin has been reported to alleviate I/R injury in the heart, brain, and small intestine in rats and mice through its anti-inflammatory effects. The present study investigated whether emodin improved AKI induced by I/R and elucidated the molecular mechanisms. We used a mouse model of renal I/R injury and human renal tubular epithelial cell model of hypoxia/reoxygenation (H/R) injury. Ischemia/reperfusion resulted in renal dysfunction. Pretreatment with emodin ameliorated renal injury in mice following I/R injury. Emodin reduced mitochondrial-mediated apoptosis, suppressed the overproduction of mitochondrial reactive oxygen species and accelerated the recovery of adenosine triphosphate both in vivo and in vitro. Emodin prevented mitochondrial fission and restored the balance of mitochondrial dynamics. The phosphorylation of dynamin-related protein 1 (DRP1) at Ser616, a master regulator of mitochondrial fission, was upregulated in both models of I/R and H/R injury, and this upregulation was blocked by emodin. Using computational cognate protein kinase prediction and specific kinase inhibitors, we found that emodin inhibited the phosphorylation of calcium/calmodulin-dependent protein kinase II (https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1554), thereby inhibiting its kinase activity and reducing the phosphorylation of DRP1 at Ser616. The results demonstrated that emodin pretreatment could protect renal function by improving mitochondrial dysfunction induced by I/R.

• Authors: Yanqing Wang, Qian Liu, Jiaying Cai, Pin Wu, Di Wang, Yundi Shi, Tianru Huyan, Jing Su, Xuejun Li, Qi Wang, Hong Wang, Fengxue Zhang, Ok-Nam Bae, Lu Tie
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 916 Pg. 174603 (Feb 05 2022) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 34793771 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Protective Agents
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• DNM1L protein, human
• Dnm1l protein, mouse
• Dynamins
• Emodin

Topics

• Acute Kidney Injury (pathology, prevention & control)
• Animals
• Apoptosis (drug effects)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (antagonists & inhibitors, metabolism)
• Cell Line
• Disease Models, Animal
• Dynamins (antagonists & inhibitors, metabolism)
• Emodin (pharmacology, therapeutic use)
• Humans
• Male
• Mice, Inbred C57BL
• Mitochondria (drug effects)
• Mitochondrial Dynamics (drug effects)
• Oxidative Stress (drug effects)
• Phosphorylation (drug effects)
• Protective Agents (pharmacology, therapeutic use)
• Reperfusion Injury (pathology, prevention & control)
• Mice