An international study led by the UGR shows the efficacy of this treatment in slowing, delaying and/or preventing the progression of kidney disease towards renal failure in animal models of diabesity (obesity and its type 2 diabetes).
Scientists from the University of Granada (UGR), the Hospital Universitario La Paz (Madrid), and the University of Texas (USA) have taken an important step in the fight against kidney damage and its progression towards kidney failure, which is closely related to diabesity (obesity and its type 2 diabetes) and its complications.
Specifically, in two new studies recently published in the prestigious scientific journals “Journal of Clinical Medicine” and “Pharmaceuticals”, researchers have developed it in an obese and diabetic rodent model, and have shown that melatonin protects the kidney damage caused by diabesity.
The Scientists have shown that chronic administration of melatonin at doses (10 mg/kg body weight/day) prevents mitochondrial and endoplasmic reticulum disruption, which play a critical role in the development and pathogenesis of kidney cell (nephron) damage, and its progression to renal failure.
Thus, it has been shown that melatonin prevents the impairment of the function and dynamics of cellular mitochondria, decreasing the increased production of oxygen free radicals (responsible for oxidative stress). It also prevents the pathological alteration in the function of the endoplasmic reticulum (another cell cytoplasmic organelle), which in conditions of abnormally high oxidative stress is related to an increase in programmed cell death (of the nephron) leading to the loss of renal functionality, as a preliminary step to the development of renal failure and the need for hemodialysis or transplantation.
The studies coordinated by the UGR show the efficacy of melatonin in halting the progression of renal damage mediated by mitochondrial damage and excess endoplasmic reticulum stress.
As the lead author of this study, Ahmad Agil, a researcher at the Department of Pharmacology of the UGR, explains, “kidney damage is caused by the metabolic complications of obesity, such as diabetes, hypertension, blood lipid disorders or fatty liver disease. Given that the prevalence of these pathologies (collectively recognized as metabolic syndrome) continues to increase, kidney damage and its progression over time to kidney failure has become a health problem that affects millions of people worldwide, with a great socioeconomic cost, requiring hemodialysis facilities and/or kidney transplant services, with the corresponding compatibility studies required”.
The importance of the work lies not only in the efficacy of melatonin in counteracting the two proposed mechanisms of renal damage (based on the one hand on the alteration of mitochondrial function and dynamics, and on the other hand on the function of the endoplasmic reticulum (ER)), but they also propose an alternative preventive treatment that would improve this renal function with a well-studied drug with a very high safety profile such as melatonin, which is a drug that in the EU must be prescribed by a doctor and is already administered in the treatment of insomnia.
The new findings have also been associated with an improvement in glomerular filtration rate and renal damage of the nephron, manifested in a decrease in creatinine clearance levels (the best marker of renal function), proteinuria, and in the improvement of renal structure, observed after histopathological study of the kidney.
These results are in line with those previously published by these researchers in the last 10 years, demonstrating that the pharmacological administration of melatonin constitutes another new strategy in the therapeutic approach to diabesity (central obesity and its type 2 diabetes) and its complications (such as hepatic steatosis, hypertension, lipid alteration, etc.).
“Our main challenge is the application of melatonin and other strategies such as intermittent fasting in the field of medicine, especially to address the possibility of a treatment perspective for the aforementioned pathologies (diabesity and its complications) that involve an increase in oxidative stress, and mitochondrial damage and associated meta-inflammation (inflammation of metabolic origin),” Agil points out.
According to the results indicated by these researchers, melatonin could help treat kidney damage, which establishes the need to develop new clinical trials to test its effectiveness in humans. The encouraging results obtained in preclinical models invite to take melatonin to the next phase, in order to investigate how it helps in the maintenance of mitochondrial and endoplasmic reticulum homeostasis, and to a greater extent, if melatonin therapy would allow delaying or stopping progressive renal damage, by promoting its chronic pharmacological use in kidney repair and regeneration.
This study has been funded by the project SAF2016-79794-R of the Ministry of Science and Innovation (Spain), and the European Regional Development Fund (ERDF) led by Professor Ahmad Agil.
Currently, the UGR research group that has developed this work is interested in collaborating with pharmaceutical companies that wish to collaborate to the commercialization of a patent, a team that is also conducting further trials with another molecule, which acts as a melatonin agonist.
This research work has been carried out by a multidisciplinary team of researchers based at the Department of Pharmacology of the UGR (Faculty of Medicine), the Institute of Neurosciences of the University of Granada, and the Biosanitary Institute of Granada), under the direction of Ahmad Agil, in collaboration with Miguel Navarro (Department of Nutrition and Bromatology of the UGR); Gumersindo Fernández (Department of Endocrinology and Nutrition, Hospital Universitario La Paz, Madrid) and Ressul Reiter, from the Department of Structural Biology (University of Texas, San Antonio, USA).
1.- Agil A,Chayah M, Visiedo L, Navarro-Alarcó M, Rodriguez Ferrer JM, Reiter JR, Fernández-Vázquez G. 2020. Melatonin improves the mitochondrial dynamics and functions in the kidney of Zuker diabetic fatty rats. J Clinical Medicine. 2020. 10;9(9):2916. doi:10.3390/ jcm9092916.
2.-Aouichat S, Navarro-Alarcon M, Alarcón P, Salagre D, Ncir M, Zourgui L, Agil A. Melatonin Improves Endoplasmic Reticulum Stress-mediated IRE1α Pathway in Zücker Diabetic Fatty Rat.Pharmaceuticals.2021. 8;14(3):232. doi: 10.3390/ph14030232.
Dr. Ahmad Agil, head of research team and member of: Institute of Neurosciences-UGR, Biosanitary Institute of Granada and.
Department of Pharmacology, University of Granada.