Quercetin Antagonizes Glucose Fluctuation Induced Renal Injury by Inhibiting Aerobic Glycolysis via HIF-1α/miR-210/ISCU/FeS Pathway

Abstract

Background and Objective: Glucose fluctuation (GF) has been reported to induce renal injury and diabetic nephropathy (DN). However, the mechanism still remains ambiguous. Mitochondrial energy metabolism, especially aerobic glycolysis, has been a hotspot of DN research for decades. The activation of HIF-1α/miR210/ISCU/FeS axis has provided a new explanation for aerobic glycolysis. Our previous studies indicated quercetin as a potential therapeutic drug for DN. This study aims to evaluate levels of aerobic glycolysis and repressive effect of quercetin via HIF-1α/miR210/ISCU/FeS axis in a cell model of GF.Methods: The mouse glomerular mesangial cells (MCs) were exposed in high or oscillating glucose with or without quercetin treatment. Cell viability was measured by CCK8 assay. Aerobic glycolysis flux was evaluated by lactate acid, pH activity of PFK. Apoptosis level was confirmed by Annexin V-APC/7-AAD double staining and activity of caspase-3. TNF-α and IL-1β were used to evaluate inflammation levels.Results: GF deteriorated inflammation damage and apoptosis injury in MCs, while quercetin could alleviate this GF-triggered cytotoxicity. GF intensified aerobic glycolysis in MCs and quercetin could inhibit this intensification in a dose-dependent manner. Quercetin prevented activities of two FeS-dependent metabolic enzymes, aconitase, and complex I, under GF injury in MCs. The mRNA expression and protein contents of HIF-1α were increased after GF exposure, and these could be alleviated by quercetin treatment. Knockdown of ISCU by siRNA and Up-regulating of miR-210 by mimic could weaken the effects of quercetin that maintained protein levels of ISCU1/2, improved cell viability, relieved inflammation injury, decreased apoptosis, and reduced aerobic glycolysis switch in MCs.Conclusion: Quercetin antagonizes GF-induced renal injury by suppressing aerobic glycolysis via HIF-1α/miR-210/ISCU/FeS pathway in MCs cell model. Our findings contribute to a new insight into understanding the mechanism of GF-induced renal injury and protective effects of quercetin.

Glucose Variability: How Does It Work?

“…Similarly, glucose fluctuations intensified aerobic glycolysis in cultured mouse mesangial cells. Oscillating glucose lowered the activity of aconitase, an enzyme of the Krebs cycle, and suppressed mitochondrial respiratory chain complex I [103]. At the same time, a reduction in the mitochondrial complex I activity was observed in the rat brain in a model of T1D [104].…”

“…The metabolic changes and dysfunction of organelles under high-GV conditions ultimately reduce the survival of a number of cells. Some in vitro studies have demonstrated the pro-apoptotic effect of IHG in endothelial cells [25,128,129], mesangial cells [103,130], cardiomyocytes [131], neurons [132,133], glial cells [134], Schwann cells [135] and beta cells [98,136]. The activation of GV-related apoptosis was attributed to mitochondrial dysfunction, ER stress and autophagy [100,124,127,131].…”

Curcumin Antagonizes Glucose Fluctuation-Induced Renal Injury by Inhibiting Aerobic Glycolysis via the miR-489/LDHA Pathway

“…In comparison to constant high- or low-glucose condition, oscillating levels of blood glucose can induce harder cytotoxicity, such as inflammatory injury, oxidative stress, and apoptosis in the fields of DN development [ 3 , 10 ] and other DM-related complication [ 47 ]. In the present study, we used HEK-293 cell to build a cellular model exposed to different high-glucose circumstances which partly mimic constant and oscillating high-glucose conditions in DM patients.…”

“…Previous studies have shown that GF condition had apoptosis-inducing and oxidative stress abilities on cells, including MCs [ 4 ], podocytes [ 5 ], and vascular endothelial cells [ 6 ]. Further, another study presented that GF increased aerobic glycolysis switch and aggravated renal injury, such as reducing cell proliferation and exacerbating inflammation and apoptosis, in a MC cell model [ 10 ]. Our results were in accordance with previous studies, and we testified the GF-related renal injury in HEK-293 cell which further verified the association between GF and DN.…”

“…Interestingly, it was found that the upregulation of the Warburg effect deeply triggered the activation of myofibroblasts and affected both the number and function of podocytes [ 8 , 9 ]. GF could deteriorate inflammation damage and apoptosis injury via intensifying the aerobic glycolysis in MC cell model [ 10 ]. These results have provided intrinsic relationships between GF, aerobic glycolysis, and DN, suggesting a potential association between the three.…”