Adiponectin protects against uric acid‑induced renal tubular epithelial inflammatory responses via the AdipoR1/AMPK signaling pathway

Yang, Qingmei; Fu, Chensheng; Zhang, Xiaoli; Zhang, Zhenxing; Zou, Jianan; Xiao, Jing; Ye, Zhibin

doi:10.3892/ijmm.2019.4072

Cited by 13 publications

(14 citation statements)

References 57 publications

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“…[7–11] In addition, the suppressive effects of adiponectin on TNF-α production have been confirmed in uric acid-insulted renal tubular epithelial cells, LPS-stimulated cardiomyocytes, and palmitic acid-exposed endothelial. [11,22,23] In the present study, LPS/D-Gal-induced production of TNF-α was suppressed by AdipoRon, which might contribute greatly to the beneficial outcomes in AdipoRon-treated animals.…”

Section: Discussionmentioning

confidence: 48%

Adiponectin receptor agonist AdipoRon relieves endotoxin-induced acute hepatitis in mice

Xiao

Zhang²

2019

Chinese Medical Journal

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Background:Adiponectin is the most abundant adipokines that plays critical roles in the maintenance of energy homeostasis as well as inflammation regulation. The half-life of adiponectin is very short and the small-molecule adiponectin receptor agonist has been synthesized recently. In the present study, the potential roles of AdipoRon, an adiponectin receptor agonist, in a mouse model of lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced acute hepatitis was explored.Methods:BALB/c mice (n = 144, male) were divided into three sets. In set 1, 32 mice were randomized into four groups: the control group, the AdipoRon group, the LPS/D-Gal group, and the AdipoRon + LPS/D-Gal group. The mice in set 1 were sacrificed after LPS/D-Gal treatment, and the plasma samples were collected for detection of tumor necrosis factor-alpha (TNF-α). In set 2, the 32 mice were also divided into four groups similar to that of set 1. The mice were sacrificed 6 h after LPS/D-Gal injection and plasma samples and liver were collected. In set 3, 80 mice (divided into four groups, n = 20) were used for survival observation. The survival rate, plasma aminotransferases, histopathological damage were measured and compared between these four groups.Results:AdipoRon suppressed the elevation of plasma aminotransferases (from 2106.3 ± 781.9 to 286.8 ± 133.1 U/L for alanine aminotransferase, P < 0.01; from 566.5 ± 243.4 to 180.1 ± 153.3 U/L for aspartate aminotransferase, P < 0.01), attenuated histopathological damage and improved the survival rate (from 10% to 60%) in mice with LPS/D-Gal-induced acute hepatitis. Additionally, AdipoRon down-regulated the production of TNF-α (from 328.6 ± 121.2 to 213.4 ± 52.2 pg/mL, P < 0.01), inhibited the activation of caspase-3 (from 2.04-fold to 1.34-fold of the control), caspase-8 (from 2.03-fold to 1.31-fold of the control), and caspase-9 (from 2.14-fold to 1.43-fold of the control), and decreased the level of cleaved caspase-3 (0.28-fold to that of the LPS/D-Gal group). The number of terminal deoxynucleotidyl transferase-mediated nucleotide nick-end labeling-positive apoptotic hepatocytes in LPS/D-Gal-exposed mice also reduced.Conclusions:These data indicated that LPS/D-Gal-induced acute hepatitis was effectively attenuated by the adiponectin receptor agonist AdipoRon, implying that AdipoRon might become a new reagent for treatment of acute hepatitis.

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Section: Discussionmentioning

confidence: 48%

Adiponectin receptor agonist AdipoRon relieves endotoxin-induced acute hepatitis in mice

Xiao

Zhang²

2019

Chinese Medical Journal

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“…We have previously demonstrated that the impairment of NKA function is one of the pivotal steps in HUA-induced renal tubular injury 6 and that AMPK activation is observed in HUA-induced renal tubular injury 23 . In our present study, we further noted that AMPK activation significantly increased NKA activity by restoring NKA cell surface expression following AICAR treatment, whereas the AMPK inhibitor Comp C exerted the opposite effects.…”

Section: Discussionmentioning

confidence: 99%

AMPK alleviates high uric acid-induced Na+-K+-ATPase signaling impairment and cell injury in renal tubules

et al. 2019

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One of the mechanisms in hyperuricemia (HUA)-induced renal tubular injury is the impairment of Na +-K +-ATPase (NKA) signaling, which further triggers inflammation, autophagy, and mitochondrial dysfunction and leads to cell injury. Here, we used RNA sequencing to screen the most likely regulators of NKA signaling and found that the liver kinase B1(LKB1)/adenosine monophosphate (AMP)-activated protein kinase (AMPK)/ mammalian target of rapamycin (mTOR) pathway was the most abundantly enriched pathway in HUA. AMPK is a key regulator of cell energy metabolism; hence, we examined the effect of AMPK on HUA-induced dysregulation of NKA signaling and cell injury. We first detected AMPK activation in high uric acid (UA)-stimulated proximal tubular epithelial cells (PTECs). We further found that sustained treatment with the AMPK activator 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR), but not the AMPK inhibitor Compound C, significantly alleviated UA-induced reductions in NKA activity and NKA α1 subunit expression on the cell membrane by reducing NKA degradation in lysosomes; sustained AICAR treatment also significantly alleviated activation of the NKA downstream molecules Src and interleukin-1β (IL-1β) in PTECs. AICAR further alleviated high UA-induced apoptosis, autophagy, and mitochondrial dysfunction. Although AMPK activation by metformin did not reduce serum UA levels in hyperuricemic rats, it significantly alleviated HUAinduced renal tubular injury and NKA signaling impairment in vivo with effects similar to those of febuxostat. Our study suggests that AMPK activation may temporarily compensate for HUA-induced renal injury. Sustained AMPK activation could reduce lysosomal NKA degradation and maintain NKA function, thus alleviating NKA downstream inflammation and protecting tubular cells from high UA-induced renal tubular injury.

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“…Moreover, soluble UA activated NLRP3 inflammasome to secrete IL-1 β in macrophages and stimulated the release of CXCL12 and HMGB1 in TECs, while interaction between macrophages and TECs promoting the progression of DN [ 108 ]. Soluble UA significantly enhanced NLRP3, tumor necrosis factor- (TNF-) α as well as IL-1 β in TECs, while AMP-activated protein kinase (AMPK) exerted a protective effect on UA-induced inflammatory response [ 120 ]. In the absence of lysosomal ruptures, mitochondria-derived ROS may mediate soluble UA-activated NLRP3 inflammasome [ 119 ].…”

Section: Mechanisms Of Hyperuricemia-induced Renal Injurymentioning

confidence: 99%

Research Advances in the Mechanisms of Hyperuricemia‐Induced Renal Injury

Yang

Liang

et al. 2020

BioMed Research International

126

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Uric acid is the end product of purine metabolism in humans, and its excessive accumulation leads to hyperuricemia and urate crystal deposition in tissues including joints and kidneys. Hyperuricemia is considered an independent risk factor for cardiovascular and renal diseases. Although the symptoms of hyperuricemia-induced renal injury have long been known, the pathophysiological molecular mechanisms are not completely understood. In this review, we focus on the research advances in the mechanisms of hyperuricemia-caused renal injury, primarily on oxidative stress, endothelial dysfunction, renal fibrosis, and inflammation. Furthermore, we discuss the progress in hyperuricemia management.

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Adiponectin protects against uric acid‑induced renal tubular epithelial inflammatory responses via the AdipoR1/AMPK signaling pathway

Cited by 13 publications

References 57 publications

Adiponectin receptor agonist AdipoRon relieves endotoxin-induced acute hepatitis in mice

Adiponectin receptor agonist AdipoRon relieves endotoxin-induced acute hepatitis in mice

AMPK alleviates high uric acid-induced Na+-K+-ATPase signaling impairment and cell injury in renal tubules

Research Advances in the Mechanisms of Hyperuricemia‐Induced Renal Injury

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