- Author: Kathy Keatley Garvey
Newly published research by an international team of scientists, headed by the Jun-Yan Liu lab of Tongji University, Shanghai, China, and the Bruce Hammock lab at the University of California, Davis, may provide promising therapeutic strategies for those suffering from acute kidney injury (AKI), formerly called acute renal failure.
AKI, common in hospitalized patients—especially among older adults in intensive care--occurs when the kidneys suddenly fail to filter waste products from the blood. Many of these patients do not recover or require dialysis or transplantation, or partly recover and are thus at risk for worsening kidney disease.
The paper, published in the current edition of the Proceedings of the National Academy of Sciences, found that a small molecule inhibitor of soluble epoxide hydrolase developed in the Hammock lab at UC Davis, helped alleviate AKI in mice and prolonged their lives.
“The soluble epoxide hydrolase or sEH degrades chemically stable fatty acid epoxides,” explained Hammock, a UC Davis distinguished professor who holds a joint appointment in the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “But sometimes it can be useful to block the function of sEH, so that beneficial fatty acid epoxides, like those from omega-3 and omega-6 fatty acids, are not degraded. These fatty acid epoxides have been found to protect the kidney, reduce inflammation, inflammatory pain, and even chronic or neuropathic pain.”
In general, the epoxides of docosahexaenoic acid (DHA) from fish oil make the soluble epoxide hydrolase inhibitors even more effective, the Hammock lab has found. “However, in this case, the fish oil seemed to be deleterious rather than beneficial when combined with the sEH inhibitors with kidney injury,” Hammock said. This was unexpected and the investigators caution that fish oil may not always have beneficial effects.
Professor Jun-Yan Liu, a former postgraduate researcher and assistant project scientist in the Hammock lab, related that the lipid mediators that preserve the kidney in AKI are termed EETs. “Their levels can be changed by altering their degradation or biosynthesis with selective inhibitors. This increase in EET resulted in anticipated decreases in the plasma level of creatinine and urea nitrogen—both biomarkers for kidney injury.” He added that they are looking forward to the epoxide hydrolase inhibitors finishing phase I clinical trials in humans so they can be evaluated for preventing or treating AKI.
Specifically, the researchers discovered that a 14(15)-EET mitigated kidney injury and prolonged life, while another epoxide, 19(20)-EDP from fish oil, exacerbated the kidney injury and shortened life. “We found that epoxides of docosahexaenoic acid (DHA) and DHA-enriched fish oil worsened kidney injury prophylactically and therapeutically in multiple animal models of AKI,” wrote Liu, pointing out that fish oil has proven beneficial in a number of other investigations.
Statistics show that “the incidence of AKI in hospitalized patients increased dramatically from 4.9 percent in 1983 to 20 percent in 2012,” the researchers wrote in their paper. “The mortality from AKI is greater than 50 percent; worldwide, approximately 2 million people die of AKI every year. Therefore, novel, safe and effective approaches are urgently needed to prevent and treat AKI.”
“Because AKI has no specific effective therapy and treatment is merely supportive frequently requiring hemodialysis any new treatment or therapeutic paradigm would be welcome in the nephrology community and has the potential to improve the lives of many patients with AKI,” said kidney expert Dr. Robert Weiss, a professor of medicine in the UC Davis Division of Nephrology, who was not involved in the research.
Kidney injury expert Alan Parrish of the University of Missouri's School of Medicine, Columbia, also not involved in the research, called the findings “significant.”
“The collaborative studies between Dr. Liu's and Hammock's group are an elegant, and timely, contribution to our understanding of acute kidney injury (AKI),” said Parrish, vice chair for education and director of Graduate Studies for Medical Pharmacology at the medical school. “AKI has potentially devastating short-term consequences - high mortality - as well as the detrimental long-term impact on renal function. Importantly, specific interventions to treat AKI in patients have not yet been identified. These results are significant in that they provide a unique mechanistic insight into pathways targeted by soluble epoxide hydrolase inhibitors that attenuate AKI, providing a powerful rationale for future clinical trials in AKI patients.”
The paper is the work of scientists led by Jun-Yan Liu from the Center for the Nephrology and Metabolomics and Division of Nephrology and Rheumatology, Tongji University School of Medicine, Shanghai, China: Bing-Qing Deng, Ying Luo, Xin Kang, Chang-Bin Li, Jian Huang, Da-Yong Hu, Ming-Yu Wu, and Ai Peng; and Hammock and his lab researchers Jun Yang, Christophe Morrisseau, Kin Sing Stephen Lee at UC Davis.
- Author: Kathy Keatley Garvey
The researchers found that a chemical inhibitor of a soluble epoxide hydrolase may be a new, innovative tool to control depression, a severe and chronic psychiatric disease that affects 350 million persons worldwide.
Soluble epoxide hydrolase, or sEH, is emerging as a therapeutic target that acts on a number of inflammatory or inflammation-linked diseases, said NIEHS grantee Bruce Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology, and the UC Davis Comprehensive Cancer Center.
“The research in animal models of depression suggests that sEH plays a key role in modulating inflammation, which is involved in depression,” Hammock said. “Inhibitors of sEH protect natural lipids in the brain that reduce inflammation, and neuropathic pain. Thus, these inhibitors could be potential therapeutic drugs for depression.”
Researchers from Hammock's laboratory collaborated with depression expert Kenji Hashimoto and colleagues at the Chiba University Center for Forensic Mental Health, Japan. The scientists observed mice for depression-like behavior after repeated social stress.
NIEHS singled out the depression research as one of its four top papers of the month. It headlined the work “Anti-Inflammatory Chemical May Offer New Tool for Depression Treatment,” in its May newsletter.
“Researchers found that the sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU), displayed rapid antidepressant effects in mice,” according to the NIEHS summary. “Researchers observed mice for depression-like behavior after repeated social stress. They found that administering TPPU reduced depression-like behaviors. Inhibiting sEH in the mice also produced resilience to the repeated stress.”
“The researchers also observed higher levels of sEH expression in key brain regions of the chronically stressed mice than in mice not subject to repeated stress,” NIEHS wrote. “They then examined postmortem human brain samples from patients with psychiatric diseases, including depression.
The work, published March 14 in the journal Proceedings of the National Academy of Sciences, drew international attention.
Other authors on the paper are Christophe Morisseau, Karen Wagner and Jun Yang, UC Davis; and Qian Ren, Min Ma, Tamaki Ishima, Ji-chun Zhang, Chun Yang, Wei Yao, Chao Dong, and Mei Han, Chiba University.