Melatonin Attenuates Cisplatin-Induced Acute Kidney Injury through Dual Suppression of Apoptosis and Necroptosis

Abstract

Melatonin is well known to modulate the sleep–wake cycle. Accumulating evidence suggests that melatonin also has favorable effects such as anti-oxidant and anti-inflammatory properties in numerous disease models. It has been reported that melatonin has therapeutic effects against cisplatin-induced acute kidney injury (AKI). However, mechanisms underlying the therapeutic action of melatonin on the renal side-effects of cisplatin therapy remain poorly understood. In this study, we showed that melatonin treatment significantly ameliorates cisplatin-induced acute renal failure and histopathological alterations. Increased expression of tubular injury markers was largely reduced by melatonin. Melatonin treatment inhibited caspase-3 activation and apoptotic cell death. Moreover, protein levels of key components of the molecular machinery for necroptosis were decreased by melatonin. Melatonin also attenuated nuclear factor-κB activation and suppressed expression of pro-inflammatory cytokines. Consistent with in vivo findings, melatonin dose-dependently decreased apoptosis and necroptosis in cisplatin-treated mouse renal tubular epithelial cells. Collectively, our findings suggest that melatonin ameliorates cisplatin-induced acute renal failure and structural damages through dual suppression of apoptosis and necroptosis. These results reveal a novel mechanism underlying the therapeutic effect of melatonin against cisplatin-induced AKI and strengthen the idea that melatonin might be a promising therapeutic agent for the renal side-effects of cisplatin therapy.

Protective Effects of Melatonin Against Aristolochic Acid-Induced Nephropathy in Mice

“…We found that melatonin significantly suppressed the elevated expression of the cytokines with inhibition of NF-κB activation in the kidneys of mice treated with AA. Consistent with these findings, we recently reported that melatonin inhibited NF-κB signaling pathway and cytokine expression in cisplatin-induced AKI [6]. Altogether, these findings suggest that melatonin effectively inhibits AA-induced inflammatory responses through modulating immune cell infiltration and activity.…”

“…Such effects of AA were effectively suppressed by melatonin. In line with our findings, melatonin has been shown to exert anti-apoptotic effects in animal models of AKI [6][7][8]. In order to obtain further mechanistic insights into the anti-apoptotic effects of melatonin, we performed Western blot analysis to assess protein levels of p53 in the kidneys, because p53 knockout mice were resistant to AA-induced apoptosis of tubular epithelial cells [29].…”

“…The Veh group was intraperitoneally injected with an equal volume of DMSO. To investigate the effects of melatonin (Sigma-Aldrich, St. Louis, MO, USA) on AAN, the AA + MEL group was intraperitoneally injected with melatonin (20 mg/kg) [6,17] from 2 days before the first injection of AA for 16 consecutive days. The mice were sacrificed 14 days after the first injection of AA.…”

“…A previous study reported that administration of exogenous melatonin ameliorated renal injury and dysfunction in pinealectomized rats [5]. It has also been shown that melatonin displays protective effects in various types of acute kidney injury (AKI) [6][7][8][9][10][11] and chronic kidney disease (CKD) [12][13][14][15]. However, the effects of melatonin on AAN have not yet been investigated.…”

Protective Effects of SPA0355, a Thiourea Analogue, Against Lipopolysaccharide-Induced Acute Kidney Injury in Mice

“…Tubular injury in PAS-stained sections was analyzed in 10 randomly chosen fields per each kidney at ×400 magnification. The tubular injury score was calculated based on the percentage of damaged area, as follows: 0, 0%; 1, ≤10%; 2, 11–25%; 3, 26–45%; 4, 46–75%; and 5, 76–100% [ 14 , 15 ]. In addition, outer diameters of proximal and distal tubules were measured in 30 randomly chosen tubules per each kidney at ×400 magnification.…”