HINT2 may be One Clinical Significance Target for Patient with Diabetes Mellitus and Reduced ROS-Induced Oxidative Stress and Ferroptosis by MCU

 

 Buy Article Permissions and Reprints

Abstract

The World Health Organization (WHO) predicted that patients with diabetes around the world will increase to 600 million by 2040, of which about 1/3 will develop diabetic nephropathy (DN). Therefore, the present study aimed to uncover therapeutic effect of HINT2 and determined its possible mechanisms. Patients with diabetes mellitus and normal volunteers were enrolled at our hospital. Male C57BL/6 mice were fed with a high fat diet and injected intraperitoneally with STZ for once (100 mg/kg body weight). Mouse podocytes (MPC5) cells were induced with 20 mmol/l D-glucose. Inhibition of HINT2 mRNA expression levels in patients with DN was observed, compared with normal group. The serum of HINT2 mRNA expression was negative in correlation with blood sugar, tubulo-interstitial damage, glomerular damage score or urine protein level in patients with DN. HINT2 expression in kidney tissue of mice with DN were downregulated. HINT2 presented reduced DN and inflammation and ROS-induced oxidative stress in model of DN. HINT2 promoted ferroptosis in model of DN by mitochondrial membrane potential. HINT2 suppressed MCU expression in model of DN. HINT2 protein combined with MCU protein increased MCU protein ubiquitination. HINT2 triggers mitochondrial Ca2+ influx to increase ROS production level by MCU. Taken together, these findings demonstrated that HINT2 reduced ROS-induced Oxidative stress and ferroptosis by MCU, suggesting that HINT2 may be a feasible strategy to treat DN.

Publication History

Received: 23 October 2022

Accepted after revision: 15 December 2023

Article published online:
29 January 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 Ajjan RA, Hensor EMA, Del Galdo F. et al. Oral 11β-HSD1 inhibitor AZD4017 improves wound healing and skin integrity in adults with type 2 diabetes mellitus: a pilot randomised controlled trial. Eur J Endocrinol 2022; 186: 441-455
  CrossrefPubMedGoogle Scholar
• 2 Birabaharan M, Kaelber DC, Pettus JH. et al. Risk of new-onset type 2 diabetes Mellitus in 600,055 persons after COVID-19: a cohort study. Diabetes Obes Metab 2022; 24: 1176-1179
  CrossrefPubMedGoogle Scholar
• 3 Jensen OC, Flores A, Corman V. et al. Rethinking the use of urine dipstick for early diagnosis of type 2 diabetes mellitus. Diabetes Res Clin Pract 2022; 174: 109222
  CrossrefPubMedGoogle Scholar
• 4 Laniado N, Khambaty T, Hua S. et al. Periodontal disease and incident prediabetes and diabetes: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). J Clinl Periodontol 2022; 49: 313-321
  CrossrefPubMedGoogle Scholar
• 5 An Y, Zhang H, Wang C. et al. Activation of ROS/MAPKs/NF-κB/NLRP3 and inhibition of efferocytosis in osteoclast-mediated diabetic osteoporosis. FASEB J 2019; 33: 12515-12527
  CrossrefPubMedGoogle Scholar
• 6 Fiorentino TV, Prioletta A, Zuo P. et al. Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Curr Pharmaceut Design 2013; 19: 5695-5703
  CrossrefPubMedGoogle Scholar
• 7 Gerber PA, Rutter GA. The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus. Antioxid Redox Signal 2017; 26: 501-518
  CrossrefPubMedGoogle Scholar
• 8 Han D, Jiang L, Gu X. et al. SIRT3 deficiency is resistant to autophagy-dependent ferroptosis by inhibiting the AMPK/mTOR pathway and promoting GPX4 levels. J Cell Physiol 2020; 235: 8839-8851
  CrossrefPubMedGoogle Scholar
• 9 Hao L, Mi J, Song L. et al. SLC40A1 mediates ferroptosis and cognitive dysfunction in type 1 diabetes. Neuroscience 2021; 463: 216-226
  CrossrefPubMedGoogle Scholar
• 10 Sha W, Hu F, Xi Y. et al. Mechanism of ferroptosis and its role in type 2 diabetes mellitus. J Diabetes Res 2021; DOI: 10.1155/2021/9999612.
  CrossrefPubMedGoogle Scholar
• 11 Li D, Jiang C, Mei G. et al. Quercetin alleviates ferroptosis of pancreatic β cells in type 2 diabetes. Nutrients 2020; 12: 2954
  CrossrefPubMedGoogle Scholar
• 12 Jia R, Chai P, Wang S. et al. m(6)A modification suppresses ocular melanoma through modulating HINT2 mRNA translation. Mol Cancer 2019; 18: 161
  CrossrefPubMedGoogle Scholar
• 13 Li S, Chen J, Liu M. et al. Protective effect of HINT2 on mitochondrial function via repressing MCU complex activation attenuates cardiac microvascular ischemia-reperfusion injury. Basic Res Cardiol 2021; 116: 65
  CrossrefPubMedGoogle Scholar
• 14 Zhou DK, Qian XH, Cheng J. et al. Clinical significance of down-regulated HINT2 in hepatocellular carcinoma. Medicine 2019; 98: e17815
  CrossrefPubMedGoogle Scholar
• 15 Li W, Cai S, Wang L. et al. HINT2 downregulation promotes colorectal carcinoma migration and metastasis. Oncotarget 2017; 8: 13521-13531
  CrossrefPubMedGoogle Scholar
• 16 Mekonnen EG, Gonete AT, Takele WW. Sexual health-seeking behaviour and associated factors in men with diabetes mellitus attending the northwest Amhara region hospitals, Ethiopia: a cross-sectional study. BMJ Open 2022; 12: e049584
  CrossrefPubMedGoogle Scholar
• 17 Nguyen HD, Oh H, Kim MS. Higher intakes of nutrients are linked with a lower risk of cardiovascular diseases, type 2 diabetes mellitus, arthritis, and depression among Korean adults. Nutr Research (New York, NY) 2021; 100: 19-32
  CrossrefPubMedGoogle Scholar
• 18 Shang Y, Zhang Y, Leng W. et al. Assessment of right ventricular function using cardiovascular magnetic resonance in patients with type 2 diabetes mellitus. Quant Imag. Med Surg 2022; 12: 1539-1548
  PubMedGoogle Scholar
• 19 Sobot NM, Sobot TS, Jeremic JN. et al. Minocycline as heart conditioning agent in experimental type 2 diabetes mellitus - an antibacterial drug in heart protection. Naunyn-Schmiedebergs Arch Pharmacol 2022; 395: 429-444
  CrossrefPubMedGoogle Scholar
• 20 Lenglet S, Antigny F, Vetterli L, Dufour JF, Rossier MF. Hint2 is expressed in the mitochondria of H295R cells and is involved in steroidogenesis. Endocrinology 2008; 149: 5461-5469
  CrossrefPubMedGoogle Scholar
• 21 Rehman K, Akash MSH. Mechanism of generation of oxidative stress and pathophysiology of type 2 diabetes mellitus: how are they interlinked?. J Cell Biochem 2017; 118: 3577-3585
  CrossrefPubMedGoogle Scholar
• 22 Rendra E, Riabov V, Mossel DM. et al. Reactive oxygen species (ROS) in macrophage activation and function in diabetes. Immunobiology 2019; 224: 242-253
  CrossrefPubMedGoogle Scholar
• 23 Wang X, Hai CX. ROS acts as a double-edged sword in the pathogenesis of type 2 diabetes mellitus: is Nrf2 a potential target for the treatment?. Mini Rev Med Chem 2011; 11: 1082-1092
  CrossrefPubMedGoogle Scholar
• 24 Chen L, Sun Q, Zhou D. et al. HINT2 triggers mitochondrial Ca(2+ ) influx by regulating the mitochondrial Ca(2+ ) uniporter (MCU) complex and enhances gemcitabine apoptotic effect in pancreatic cancer. Cancer Lett 2017; 411: 106-116
  CrossrefPubMedGoogle Scholar
• 25 Zhou RP, Chen Y, Wei X. et al. Novel insights into ferroptosis: implications for age-related diseases. Theranostics 2020; 10: 11976-11997
  CrossrefPubMedGoogle Scholar
• 26 Gleitze S, Paula-Lima A, Núñez MT. et al. The calcium-iron connection in ferroptosis-mediated neuronal death. Free Rad. Biol Med 2021; 175: 28-41
  PubMedGoogle Scholar
• 27 Nakamura T, Ogawa M, Kojima K. et al. The mitochondrial Ca(2+ ) uptake regulator, MICU1, is involved in cold stress-induced ferroptosis. EMBO Rep 2021; 22: e51532
  CrossrefPubMedGoogle Scholar
• 28 Shui S, Zhao Z, Wang H. et al. Non-enzymatic lipid peroxidation initiated by photodynamic therapy drives a distinct ferroptosis-like cell death pathway. Redox Biol 2021; 45: 102056
  CrossrefPubMedGoogle Scholar
• 29 Boyman L, Greiser M, Lederer WJ. Calcium influx through the mitochondrial calcium uniporter holocomplex, MCU(cx). J Mol Cell Cardiol 2021; 151: 145-154
  CrossrefPubMedGoogle Scholar
• 30 Zhao H, Li T, Wang K. et al. AMPK-mediated activation of MCU stimulates mitochondrial Ca(2+ ) entry to promote mitotic progression. Nat Cell Biol 2019; 21: 476-486
  CrossrefPubMedGoogle Scholar