Melatonin attenuates acute kidney ischemia/reperfusion injury in diabetic rats by activation of the SIRT1/Nrf2/HO-1 signaling pathway

Abstract

Background and aims: Diabetic kidney is more sensitive to ischemia/reperfusion (I/R) injury, which is associated with increased oxidative stress and impaired nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling. Melatonin, a hormone that is secreted with the rhythm of the light/dark cycle, has antioxidative effects in reducing acute kidney injury (AKI). However, the molecular mechanism of melatonin protection against kidney I/R injury in the state of diabetes is still unknown. In the present study, we hypothesized that melatonin attenuates renal I/R injury in diabetes by activating silent information regulator 2 associated protein 1 (SIRT1) expression and Nrf2/HO-1 signaling. Methods: Control or streptozotocin (STZ)-induced Type 1 diabetic rats were treated with or without melatonin for 4 weeks. Renal I/R injury was achieved by clamping both left and right renal pedicles for 30 min followed by reperfusion for 48 h. Results: Diabetic rats that were treated with melatonin undergoing I/R injury prevented renal injury from I/R, in aspects of the histopathological score, cell apoptosis, and oxidative stress in kidney, accompanied with decreased expressions of SIRT1, Nrf2, and HO-1 as compared with those in control rats. All these alterations were attenuated or prevented by melatonin treatment; but these beneficial effects of melatonin were abolished by selective inhibition of SIRT1 with EX527. Conclusion: These findings suggest melatonin could attenuate renal I/R injury in diabetes, possibly through improving SIRT1/Nrf2/HO-1 signaling.

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

“…Altogether, these results suggest that modulation of pro-oxidant and antioxidant enzymes by melatonin presumably contributes, at least in part, to its protective effect against AA-induced oxidative injury. In good agreement with our findings, melatonin has been shown to suppress oxidative stress and regulate pro-oxidant and antioxidant enzymes in animal models of AKI [8][9][10][11] and CKD [12][13][14]. Besides, the hormone is well known to have potent ROS-scavenging activity [3].…”

“…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].…”

“…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.…”

Melatonin: new insights on its therapeutic properties in diabetic complications

“…In a 4-week in vivo study, Shi et al evaluated the therapeutic effects of melatonin on renal I/R of diabetic rats. Animals were treated with or without melatonin, and renal I/R injury was induced by clamping right and left renal pedicles for 30 min followed by reperfusion for 48 h. Diabetic rats treated with melatonin were protected against renal injury, in aspects of oxidative stress and cell apoptosis in kidney [174].…”

Inhibition of the SIRT1 signaling pathway exacerbates endoplasmic reticulum stress induced by renal ischemia/reperfusion injury in type 1 diabetic rats

“…evidence has accumulated supporting the fact that dM aggravates renal i/r injury (5). experimental studies have revealed that diabetic rats develop renal dysfunction faster following ir injury compared with non-diabetic rats (6,7). other research has revealed that progressive hyperglycemia can cause increased levels of reactive oxygen species (roS) in the diabetic kidney following i/r injury (8).…”