HIF‐1α ameliorates tubular injury in diabetic nephropathy via HO‐1–mediated control of mitochondrial dynamics

Jiang, Na; Zhao, Hao; Han, Yachun; Li, Li; Xiong, Shan; Zeng, Lingfeng; Xiao, Ying; Wei, Ling; Xiong, Xiaofen; Gao, Peng; Yang, Ming; Liu, Yu; Sun, Lin

doi:10.1111/cpr.12909

Cited by 84 publications

(62 citation statements)

References 63 publications

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“…HIF-1α and HO-1 have been demonstrated to serve the dual roles in multiple models of kidney injury, including DN. There have been some studies about the significant protective role of HIF-1α/HO-1 pathway ( 43 ). However, several recent studies have validated the promoted HIF-1α and HO-1 levels in kidneys of diabetic models ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis Enhanced Diabetic Renal Tubular Injury via HIF-1α/HO-1 Pathway in db/db Mice

et al. 2021

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BackgroundFerroptosis is a recently identified iron-dependent form of cell death as a result of increased reactive oxygen species (ROS) and lipid peroxidation. In this study, we investigated whether ferroptosis aggravated diabetic nephropathy (DN) and damaged renal tubules through hypoxia-inducible factor (HIF)-1α/heme oxygenase (HO)-1 pathway in db/db mice.MethodsDb/db mice were administered with or without ferroptosis inhibitor Ferrostatin-1 treatment, and were compared with db/m mice.ResultsDb/db mice showed higher urinary albumin-to-creatinine ratio (UACR) than db/m mice, and Ferrostatin-1 reduced UACR in db/db mice. Db/db mice presented higher kidney injury molecular-1 and neutrophil gelatinase-associated lipocalin in kidneys and urine compared to db/m mice, with renal tubular basement membranes folding and faulting. However, these changes were ameliorated in db/db mice after Ferrostatin-1 treatment. Fibrosis area and collagen I were promoted in db/db mouse kidneys as compared to db/m mouse kidneys, which was alleviated by Ferrostatin-1 in db/db mouse kidneys. HIF-1α and HO-1 were increased in db/db mouse kidneys compared with db/m mouse kidneys, and Ferrostatin-1 decreased HIF-1α and HO-1 in db/db mouse kidneys. Iron content was elevated in db/db mouse renal tubules compared with db/m mouse renal tubules, and was relieved in renal tubules of db/db mice after Ferrostatin-1 treatment. Ferritin was increased in db/db mouse kidneys compared with db/m mouse kidneys, but Ferrostatin-1 reduced ferritin in kidneys of db/db mice. Diabetes accelerated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived ROS formation in mouse kidneys, but Ferrostatin-1 prevented ROS formation derived by NADPH oxidases in db/db mouse kidneys. The increased malondialdehyde (MDA) and the decreased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GSH-Px) were detected in db/db mouse kidneys compared to db/m mouse kidneys, whereas Ferrostatin-1 suppressed MDA and elevated SOD, CAT, and GSH-Px in db/db mouse kidneys. Glutathione peroxidase 4 was lower in db/db mouse kidneys than db/m mouse kidneys, and was exacerbated by Ferrostatin-1 in kidneys of db/db mice.ConclusionsOur study indicated that ferroptosis might enhance DN and damage renal tubules in diabetic models through HIF-1α/HO-1 pathway.

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Section: Discussionmentioning

confidence: 99%

Ferroptosis Enhanced Diabetic Renal Tubular Injury via HIF-1α/HO-1 Pathway in db/db Mice

et al. 2021

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“…Our finding provided the evidence that swing of glucose also induced abnormal expression of miR-210 in a mouse glomerular MCs cell line. Considering HIF-1α/miR-210 are involving in GF ( 11 ), DN ( 12 ), and Warburg effect ( 13 ), it is reasonable to believe that this axis may be a vital target in the treatment of GF-related damage and the prevention of DN. ISCU/FeS pathway is the down-stream target of HIF-1α/miR-210.…”

Section: Discussionmentioning

confidence: 99%

“…Disturbance of FeS assembly contributes to the development of DN via inactivation of FeS-dependent enzymes, such as complex I ( 10 ). HIF-1α is also considered to play roles among GF ( 11 ), DN ( 12 ), and Warburg effect ( 13 ). Mitochondria are the major sites for regulating glucose metabolism of cells.…”

Section: Introductionmentioning

confidence: 99%

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

Liu

et al. 2021

Front. Med.

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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.

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“…The expression of HIF-1α is increased in diabetic mice. Conditional deletion of HIF-1α in proximal tubular cells of STZ-induced diabetic mice enhances kidney injury and mitochondrial fission by increasing Drp1, phosphorylated Drp-1, and Fis1 [ 75 ]. Moreover, HIF-1α regulates heme oxygenase-1 (HO-1) expression directly [ 75 ].…”

Section: Recent Advances On Mitochondrial Fission In Diabetic Nephropathymentioning

confidence: 99%

Excessively Enlarged Mitochondria in the Kidneys of Diabetic Nephropathy

Kim

Lee

2021

Antioxidants

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Diabetic nephropathy (DN) is the most serious complication of diabetes and a leading cause of kidney failure and mortality in patients with diabetes. However, the exact pathogenic mechanisms involved are poorly understood. Impaired mitochondrial function and accumulation of damaged mitochondria due to increased imbalance in mitochondrial dynamics are known to be involved in the development and progression of DN. Accumulating evidence suggests that aberrant mitochondrial fission is involved in the progression of DN. Conversely, studies linking excessively enlarged mitochondria to DN pathogenesis are emerging. In this review, we summarize the current concepts of imbalanced mitochondrial dynamics and their molecular aspects in various experimental models of DN. We discuss the recent evidence of enlarged mitochondria in the kidneys of DN and examine the possibility of a therapeutic application targeting mitochondrial dynamics in DN.

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HIF‐1α ameliorates tubular injury in diabetic nephropathy via HO‐1–mediated control of mitochondrial dynamics

Cited by 84 publications

References 63 publications

Ferroptosis Enhanced Diabetic Renal Tubular Injury via HIF-1α/HO-1 Pathway in db/db Mice

Ferroptosis Enhanced Diabetic Renal Tubular Injury via HIF-1α/HO-1 Pathway in db/db Mice

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

Excessively Enlarged Mitochondria in the Kidneys of Diabetic Nephropathy

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