Melatonin inhibits oxalate-induced endoplasmic reticulum stress and apoptosis in HK-2 cells by activating the AMPK pathway

Song, Qianlin; He, Ziqi; Li, Bin; Liu, Junwei; Liao, Wenbiao; Xiong, Yunhe; Song, Chao; Yang, Sixing; Liu, Yunlong

doi:10.1080/15384101.2020.1810401

Cited by 28 publications

(22 citation statements)

References 49 publications

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“…Our results are in keeping with recent findings demonstrating that melatonin reduced ER stress in different models of kidney injury. For instance, melatonin attenuated the ER stress response markers in–vitro kidney stones model [ 40 ]. Similar effects were also observed in rat model of renal ischemia/reperfusion injury [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…This mechanism could not rule out the possibility that melatonin may also depend on ER stress response and its downstream signaling mechanism to limit kidney damage under conditions of obesity and associated diabetes, given that melatonin has been shown to be effective in modulating ER stress response and UPR activation in different pathological situations [ 37 , 38 , 39 ]. With respect to kidney diseases, so far, there has been only two studies, in which melatonin was able to reduce renal ER stress in human in–vivo kidney stones model [ 40 ] and in a rat model of renal warm ischemia–reperfusion [ 41 ]. However, whether melatonin can mitigate renal ER stress in a rat model of obesity and diabetes-associated kidney injury has not yet been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Melatonin Improves Endoplasmic Reticulum Stress-Mediated IRE1α Pathway in Zücker Diabetic Fatty Rat

et al. 2021

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Obesity and diabetes are linked to an increased prevalence of kidney disease. Endoplasmic reticulum stress has recently gained growing importance in the pathogenesis of obesity and diabetes-related kidney disease. Melatonin, is an important anti-obesogenic natural bioactive compound. Previously, our research group showed that the renoprotective effect of melatonin administration was associated with restoring mitochondrial fission/fusion balance and function in a rat model of diabesity-induced kidney injury. This study was carried out to further investigate whether melatonin could suppress renal endoplasmic reticulum (ER) stress response and the downstream unfolded protein response activation under obese and diabetic conditions. Zücker diabetic fatty (ZDF) rats and lean littermates (ZL) were orally supplemented either with melatonin (10 mg/kg body weight (BW)/day) (M–ZDF and M–ZL) or vehicle (C–ZDF and C–ZL) for 17 weeks. Western blot analysis of ER stress-related markers and renal morphology were assessed. Compared to C–ZL rats, higher ER stress response associated with impaired renal morphology was observed in C–ZDF rats. Melatonin supplementation alleviated renal ER stress response in ZDF rats, by decreasing glucose-regulated protein 78 (GRP78), phosphoinositol-requiring enzyme1α (IRE1α), and ATF6 levels but had no effect on phospho–protein kinase RNA–like endoplasmic reticulum kinase (PERK) level. In addition, melatonin supplementation also restrained the ER stress-mediated apoptotic pathway, as indicated by decreased pro-apoptotic proteins phospho–c–jun amino terminal kinase (JNK), Bax, and cleaved caspase-3, as well as by upregulation of B cell lymphoma (Bcl)-2 protein. These improvements were associated with renal structural recovery. Taken together, our findings revealed that melatonin play a renoprotective role, at least in part, by suppressing ER stress and related pro-apoptotic IRE1α/JNK signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Melatonin Improves Endoplasmic Reticulum Stress-Mediated IRE1α Pathway in Zücker Diabetic Fatty Rat

et al. 2021

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“…After cell intervention, the corresponding reagents were added according to the manufacturer's instructions. The detailed steps are described in our previous study [ 3 ]. A microplate reader was used to detect the absorbance of each well at a wavelength of 490 nm.…”

Section: Methodsmentioning

confidence: 99%

“…The relative gene expression level of the target genes was determined using the formula: ratio = (1 + E target ) ΔCt target(control − expt)/ (1 + E reference ) ΔCt reference(control − expt) . The specific steps were described in detail in our previous study [ 3 ]. The primer sequences of the target genes were as follows: GAPDH forward 5′-GTCTCCTCTGACTTCAACAGCG-3′ and reverse 5′-ACCACCCTGTTGCTGTAGCCAA-3′; BECN1 forward 5′-CTGGACACTCAGCTCAACGTCA-3′ and reverse 5′-CTCTAGTGCCAGCTCCTTTAGC-3′; GPX4 forward 5′-ACAAGAACGGCTGCGTGGTGAA-3′ and reverse 5′-GCCACACACTTGTGGAGCTAGA-3′; and NCOA4 forward 5′-GCTTGCTATTGGTGGAGTTCTCC-3′ and reverse 5′-GCCATACCTCACGGCTTCTAAG-3′.…”

Section: Methodsmentioning

confidence: 99%

“…Kidney stones are one of the most common diseases in urology, representing a burden on global public health [ 1 , 2 ]. Epidemiological surveys show that the global incidence of kidney stones is 1.7–14.8%, and the 5-year recurrence rate of kidney stones can be as high as 50% [ 3 ]. The high rate of recurrence of calculi has resulted in kidney stones being considered a systemic chronic disease [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

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Oxalate Activates Autophagy to Induce Ferroptosis of Renal Tubular Epithelial Cells and Participates in the Formation of Kidney Stones

Song

Liao

Chen

et al. 2021

Oxidative Medicine and Cellular Longevity

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Renal tubular epithelial cell damage is the basis for the formation of kidney stones. Oxalate can induce human proximal tubular (HK-2) cells to undergo autophagy and ferroptosis. The present study was aimed at investigating whether the ferroptosis of HK-2 cells induced by oxalate is caused by the excessive activation of autophagy. We treated HK-2 cells with 2 mmol/L of oxalate to establish a kidney stone model. First, we tested the degree of oxidative damage and the level of autophagy and ferroptosis in the control group and the oxalate intervention group. We then knocked down and overexpressed the BECN1 gene and knocked down the NCOA4 gene in HK-2 cells, followed by redetection of the above indicators. We confirmed that oxalate could induce autophagy and ferroptosis in HK-2 cells. Moreover, after oxalate treatment, overexpression of the BENC1 gene increased cell oxidative damage and ferroptosis. In addition, knockdown of NCOA4 reversed the effect of oxalate-induced ferroptosis in HK-2 cells. Our results show that the effects of oxalate on the ferroptosis of HK-2 cells are caused by the activation of autophagy, and knockdown of the NCOA4 could ameliorate this effect.

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Molecular mechanism of Rhizoma Polygonati in the treatment of nephrolithiasis: network pharmacology analysis and in vivo experimental verification

Xu,

Liang,

Mao

et al. 2024

Urolithiasis

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Melatonin inhibits oxalate-induced endoplasmic reticulum stress and apoptosis in HK-2 cells by activating the AMPK pathway

Cited by 28 publications

References 49 publications

Melatonin Improves Endoplasmic Reticulum Stress-Mediated IRE1α Pathway in Zücker Diabetic Fatty Rat

Melatonin Improves Endoplasmic Reticulum Stress-Mediated IRE1α Pathway in Zücker Diabetic Fatty Rat

Oxalate Activates Autophagy to Induce Ferroptosis of Renal Tubular Epithelial Cells and Participates in the Formation of Kidney Stones

Molecular mechanism of Rhizoma Polygonati in the treatment of nephrolithiasis: network pharmacology analysis and in vivo experimental verification

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