Cyst Reduction by Melatonin in a Novel Drosophila Model of Polycystic Kidney Disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) causes progressive cystic degeneration of the renal tubules, the nephrons, eventually severely compromising kidney function. ADPKD is incurable, with half of the patients eventually needing renal replacement. Treatments for ADPKD patients are limited and new effective therapeutics are needed. Melatonin, a central metabolic regulator conserved across all life kingdoms, exhibits oncostatic and oncoprotective activity and no detected toxicity. Here, we used the Bicaudal C (BicC) Drosophila model of polycystic kidney disease to test the cyst-reducing potential of melatonin. Significant cyst reduction was found in the renal (Malpighian) tubules upon melatonin administration and suggest mechanistic sophistication. Similar to vertebrate PKD, the BicC fly PKD model responds to the antiproliferative drugs rapamycin and mimics of the second mitochondria-derived activator of caspases (Smac). Melatonin appears to be a new cyst-reducing molecule with attractive properties as a potential candidate for PKD treatment.

Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

“…Parkinson disease Tang et al [194] Chen et al [195] Polycystic kidney disease Podrini et al [196] Millet-Boureima et al [197] Diabetic kidney disease Morita and Kawaski et al [198] Promsan and Lungkaphin et al [199 The altered glucose metabolism, known as the Warburg effect, was initially discovered in cancer cells [222] but within the last two decades, it has also been found to occur in non-neoplastic, diseased cells as well. In the case of tumors, reversing the Warburg effect is considered a potential target for tumor therapy and several synthetic molecules have been developed for this purpose.…”

Modeling Neoplastic Growth in Renal Cell Carcinoma and Polycystic Kidney Disease

“…Melatonin may hold promise in ADPKD therapy as well. Very recently, we published that melatonin treatment significantly reduced renal tubule cysts in the Drosophila PKD model [307]. In this study, nightly administration of 150 µM melatonin effectively decreased the cystic index of BicC flies, further suggesting the conservation of common core mechanisms of abnormal cystic and neoplastic cell growth [307].…”

“…Still a relatively untapped resource in drug studies, robust pathway conservation between Drosophila and humans and effective transgenesis enabling expression of human proteins and variants in the fly, empower pharmacological studies with translational significance. This has been particularly successful in oncology ( [328,329], reviewed in [330]) and may have potential for ADPKD [200,201,307]. Disease modeling relies on models for discovery science, preclinical models of diseased states, and models for therapeutic outcomes.…”

“…Very recently, we published that melatonin treatment significantly reduced renal tubule cysts in the Drosophila PKD model [307]. In this study, nightly administration of 150 µM melatonin effectively decreased the cystic index of BicC flies, further suggesting the conservation of common core mechanisms of abnormal cystic and neoplastic cell growth [307]. While the cyst-reducing mechanisms of melatonin are being investigated, melatonin holds special interest as a molecule to treat PKD because its lack of toxicity, high tolerability, and potential for combination therapy would be perfectly suited to the protracted treatment of chronic PKD.…”

Melatonin attenuates radiation-induced cortical bone-derived stem cells injury and enhances bone repair in postradiation femoral defect model

“…Melatonin is well known for its potent antioxidant capacity, low toxicity, and wide distribution throughout the body [30,31]. As a potent scavenger, melatonin and its metabolites can e ciently neutralize free radicals.…”