Molecular regulatory mechanisms of hypoxia-inducible factor and interventional effect of Chinese herbal medicine

LIU Bu-hui1,2 WANG Mei-zi2 SUN Wei1 WAN Yi-gang3 WU Wei3 FANG Qi-jun2 WANG Wen-wen2 YEE Hong-yun2 YUAN Can-can2 LIU Ying-lu3 TU Yue4 CHONG Fee-lan5

(1.Nephrology Department, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China 210029)
(2.Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China 210008)
(3.Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China 210008)
(4.Teaching and Research Section of Health Preservation with Traditional Chinese Medicine, Acupuncture and Moxibustion and Massage College·Health Preservation and Rehabilitation College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China 210023)
(5.The School of Pharmacy, Management and Science University, Shah Alam 40100, Malaysia)

【Abstract】Hypoxia-inducible factors (HIFs) are the key transcription factors that sense and regulate cellular oxygen concentration in vivo. HIF-1 is composed of 2 subunits, α and β. The molecular regulatory mechanism of HIF-1α involves degradation and activation. The degradation of HIF-1α is regulated by oxygen-dependent pathways, including “von hippel-lindau protein (pVHL)-dependent pathway” and “pVHL-independent pathway.” The activation of HIF-1α is regulated by oxygen-independent pathways, including mammalian target of rapamycin (mTOR)/eukaryotic initiation factor 4 E-binding protein 1 (4EBP1)/HIF-1α pathway, phosphatidylinositol 3-kinase (PI3K)/proteirrserinc-threonine kinases (Akt)/HIF-1α pathway, and silent information regulator 1 (Sirt1)/HIF-1α pathway. In recent years, based on the molecular regulatory mechanism of HIFs, roxadustat, a new drug for the treatment of renal anemia, has been developed. Besides, some macromolecular substances with similar pharmacological effects to those of HIFs have been found in the extracts from Chinese herbal medicines, such as emodin, notoginsenoside, honokiol, and clematichinenoside. These natural macromolecular substances play the regulatory roles in inflammatory response, autophagy, epigenetic modification, and pyroptosis. It is worth noting that, for common hypoxia-related diseases including diabetic kidney disease (DKD), HIFs-mediated “pyroptosis” may be a new target of heat-clearing and diuresis-inducing Chinese herbal medicines and its representative classical prescriptions (e.g., Ermiao Pills) in treating inflammatory injury in cells and tissues.

【Keywords】 hypoxia-inducible factors; Chinese herbal medicine; molecular mechanism; signaling pathway; pyroptosis;

【DOI】

【Funds】 General Programs of National Natural Science Foundation of China (81774245 and 81573903) Youth Program of National Natural Science Foundation of China (81603675) Natural Science Foundation of Jiangsu Province (BK20161046) Traditional Chinese Medicine Science and Technology Development Project of Jiangsu Province (YB201937) Project for Medical Science and Technology Development in Nanjing (QRX17042)

Download this article

    References

    [1] JAIN I H, ZAZZERON L, GOLI R, et al. Hypoxia as a therapy for mitochondrial disease [J]. Science, 2016, 352 (6281): 54.

    [2] MAKINO K, ISOE T, HANEDA M. HIF-1α [J]. The Japanese Journal of Nephrology, 2011, 53, (7), 1006 (in Japanese).

    [3] KAPLAN J. Roxadustat and anemia of chronic kidney disease [J]. N Engl J Med, 2019, 381 (11): 1070.

    [4] CHEN N, HAO C, PENG X, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis [J]. N Engl J Med, 2019, 381 (11): 1001.

    [5] PERGOLA P E, SPINOWITZ B S, HARTMAN C S, et al. Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease [J]. Kidney Int, 2016, 90 (5): 1115.

    [6] HOLDSTOCK L, MEADOWCROFT A M, MAIER R, et al. Four-week studies of oral hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 for treatment of anemia [J]. J Am Soc Nephrol, 2016, 27 (4): 1234.

    [7] BRIGANDI R A, JOHNSON B, OEI C, et al. A novel hypoxia-inducible factor-prolyl hydroxylase inhibitor (GSK1278863) for anemia in CKD: a 28-day, phase 2A randomized trial [J]. Am J Kidney Dis, 2016, 67 (6): 861.

    [8] MACDOUGALL I C, AKIZAWA T, BERNS J S, et al. Effects of molidustat in the treatment of anemia in CKD [J]. Clin J Am Soc Nephrol, 2019, 14 (1): 28.

    [9] CHEN N, QIAN J, CHEN J, et al. Phase 2 studies of oral hypo-xiainducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China [J]. Nephrol Dial Transplant, 2017, 32 (8): 1373.

    [10] CHEN N, HAO C, LIU B C, et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis [J]. N Engl J Med, 2019, 381 (11): 1011.

    [11] BRIGGS K J, KOIVUNEN P, CAO S, et al. Paracrine induction of HIF by glutamate in breast cancer: EglN1 senses cysteine [J]. Cell, 2016, 166 (1): 126.

    [12] CHAKRABORTY A A, LAUKKA T, MYLLYKOSKI M, et al. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate [J]. Science, 2019, 363 (6432): 1217.

    [13] GILKES D M, SEMENZA G L, WIRTZ D. Hypoxia and the extracellular matrix:drivers of tumor metastasis [J]. Nat Rev Cancer, 2014, 14 (6): 430.

    [14] LI X, SHAN C, WU Z, et al. Emodin alleviated pulmonary inflammation in rats with LPS-induced acute lung injury through inhibiting the mTOR/HIF-1α/VEGF signaling pathway [J]. Inflamm Res, 2020, 69 (4): 365.

    [15] ZHOU J L, YANG Y F, HUANG Z G, et al. Effect of Panax notoginseng saponins on cisplatin-induced kidney injury by enhancing mitochondrial autophagy via the HIF-1α/ BNIP3 pathway [J]. Chinese Pharmaceutical Journal, 2017, 52 (3): 196 (in Chinese).

    [16] VAVILALA D T, PONNALURI V K, VADLAPATLA R K, et al. Honokiol inhibits HIF pathway and hypoxia-induced expression of histone lysine demethylases [J]. Biochem Biophys Res Commun, 2012, 422 (3): 369.

    [17] LI Y, ZHENG J Y, LIU J Q, et al. Succinate/NLRP3 inflammasome induces synovial fibroblast activation: therapeutical effects of clematichinenoside AR on arthritis [J]. Front Immunol, 2016, 7: 532.

    [18] SEMENZA G L, WANG G L. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation [J]. Mol Cell Biol, 1992, 12 (12): 5447.

    [19] WU D, POTLURI N, LU J, et al. Structural integration in hypoxia-inducible factors [J]. Nature, 2015, 524 (7565): 303.

    [20] ROSENBERGER C, MANDRIOTA S, JURGENSEN J, et al. Expression of hypoxia-inducible factor-1α and -2α in hypoxic and ischemic rat kidneys [J]. J Am Soc Nephrol, 2002, 13 (7): 1721.

    [21] GRUBER M, HU C J, JOHNSON R S, et al. Acute postnatal ablation of HIF-2α results in anemia [J]. Proc Natl Acad Sci USA, 2007, 104 (7): 2301.

    [22] PALIEGE A, ROSENBERGER C, BONDKE A, et al. Hypoxia-inducible factor-2α-expressing interstitial fibroblasts are the only renal cells that express erythropoietin under hypoxia-inducible factor stabilization [J]. Kidney Int, 2010, 77 (4): 312.

    [23] HAASE V H. Hypoxia-inducible factors in the kidney [J]. Am J Physiol Renal Physiol, 2006, 291 (2): F271.

    [24] CHEN S Y, SANG N L. Hypoxia-inducible factor-1: a critical player in the survival strategy of stressed cells [J]. J Cell Biochem, 2016, 117 (2): 267.

    [25] STEGEN S, VAN GASTEL N, EELEN G, et al. HIF-1α promotes glutamine-mediated redox homeostasis and glycogen-dependent bioenergetics to support postimplantation bone cell survival [J]. Cell Metab, 2016, 23 (2): 265.

    [26] BAHRAMI A, ATKIN S L, MAJEED M, et al. Effects of curcumin on hypoxia-inducible factor as a new therapeutic target [J]. Pharmacol Res, 2018, 137: 159.

    [27] GUO Y, SCHEUERMANN T H, PARTCH C L, et al.Coiled-coil coactivators play a structural role mediating interactions in hypo-xiainducible factor heterodimerization [J]. J Biol Chem, 2015, 290 (12): 7707.

    [28] WANG L, ZHANG Y L, WANG X F, et al. Expression and significance of m TOR/4EBP1/HIF-1α/VEGF signaling pathway in lung tissues of asthmatic mice [J]. Chinese Journal of Contemporary Pediatrics, 2017, 19 (1): 104 (in Chinese).

    [29] CHIEN W, LEE D H, ZHENG Y, et al. Growth inhibition of pancreatic cancer cells by histone deacetylase inhibitor belinostat through suppression of multiple pathways including HIF, NF-κB and mTOR signaling in vitro and in vivo [J]. Mol Carcinog, 2014, 53 (9): 722.

    [30] YANG C, LIU X, ZHAO K, et al. miRNA-21 promotes osteogenesis via the PTEN/PI3K/Akt/HIF-1α pathway and enhances bone regeneration in critical size defects [J]. Stem Cell Res Ther, 2019, 10 (1): 65.

    [31] TAGLIERI L, NARDO T, VICINANZA R, et al. Thyroid hormone regulates fibronectin expression through the activation of the hypoxia inducible factor 1 [J]. Biochem Biophys Res Commun, 2017, 493 (3): 1304.

    [32] LIU Y, JIANG S, CHEN X Y, et al. Effect of Hei Gu Teng Zhui Feng Huo Luo Capsule on PI3K/AKT/HIF-1α protein signaling pathway in rheumatoid arthritis rats [J]. Chinese Journal of Immunology, 2019, 35 (18): 2206 (in Chinese).

    [33] DAS A, HUANG G X, BONKOWSKI M S, et al. Impairment of an endothelial NAD+-H2S signaling network is a reversible cause of vascular aging [J]. Cell, 2018, 173 (1): 74.

    [34] ZHAO Y, YAN J, LI A P, et al. Bone marrow mesenchymal stem cells could reduce the toxic effects of hexavalent chromium on the liver by decreasing endoplasmic reticulum stress-mediated apoptosis via SIRT1/HIF-1α signaling pathway in rats [J]. Toxicol Lett, 2019, 310: 31.

    [35] SUN X H, HUANG K P, HUANG H Q. Connexin43通过SIRT1-HIF1-α通路改善糖尿病肾小管间质纤维化的研究 [J]. Chinese Journal of Pharmacology and Toxicology, 2019, 33 (9): 718 (in Chinese).

    [36] WANG Q, SU C P, ZHANG H M, et al. Anti-inflammatory mechanism of heat-clearing and detoxifying Chinese herbs [J]. China Journal of Chinese Materia Medica, 2018, 43 (18): 3787 (in Chinese).

    [37] GONZALEZ F J, XIE C, JIANG C. The role of hypoxia-inducible factors in metabolic diseases [J]. Nat Rev Endocrinol, 2018, 15 (1): 21.

    [38] TAYLOR C T, COLGAN S P. Regulation of immunity and inflammation by hypoxia in immunological niches [J]. Nat Rev Immunol, 2017, 17 (12): 774.

    [39] CAI H, SHI H Z, YANG Y X. The effects of over-expression of hypoxia inducible factor-1α on cell proliferation, inflammatory response and angiogenesis in vitro cultured human retinal capillary endothelial cells [J]. Recent Advances in Ophthalmology, 2019, 39 (1): 32 (in Chinese).

    [40] LIU M W, SU M X, ZHANG W, et al. Protective effect of Xuebijing Injection on paraquat-induced pulmonary injury via down-regulating the expression of p38 MAPK in rats [J]. BMC Complement Altern Med, 2014, 14: 498.

    [41] DASKALAKI I, GKIKAS I, TAVERNARAKIS N. Hypoxia and selective autophagy in cancer development and therapy [J]. Front Cell Dev Biol, 2018, 6: 104.

    [42] QURESHI-BAIG K, KUHN D, VIRY E, et al. Hypoxia-induced autophagy drives colorectal cancer initiation and progression by activating the PRKC/PKC-EZR (ezrin) pathway [J]. Autophagy, 2019, doi: 10.1080/15548627.2019.1687213.

    [43] YAN G W, DING Y Z, XING J F, et al. Effects of hypoxia on expressions of HIF-1α, BNIP3 and autophagy, invasion ability in trophoblasts [J]. Journal of Zhengzhou University (Medical Sciences), 2018, 53 (2): 198 (in Chinese).

    [44] HAN X, SUN S, ZHAO M, et al. Celastrol stimulates hypoxia-inducible factor-1 activity in tumor cells by initiating the ROS/Akt/p70S6K signaling pathway and enhancing hypoxia-inducible factor-1α protein synthesis [J]. PLoS ONE, 2014, 9 (11): e112470.

    [45] SACCÀ C D, GORINI F, AMBROSIO S, et al. Inhibition of lysine-specific demethylase LSD1 induces senescence in glioblastoma cells through a HIF-1α-dependent pathway [J]. Biochim Biophys Acta Gene Regul Mech, 2019, 1862 (5): 535.

    [46] CHEN F, CHEN J, YANG L, et al. Extracellular vesicle-packaged HIF-1α-stabilizing lncRNA from tumour-associated macrophages regulates aerobic glycolysis of breast cancer cells [J]. Nat Cell Biol, 2019, 21 (4): 498.

    [47] HIRAKAWA Y, TANAKA T, NANGAKU M. Mechanisms of metabolic memory and renal hypoxia as a therapeutic target in diabetic kidney disease [J]. J Diabetes Investig, 2017, 8 (3): 26.

    [48] WANG Y, ZHU X, YUAN S, et al. TLR4/NF-κB signaling induces GSDMD-related pyroptosis in tubular cells in diabetic kidney disease [J]. Front Endocrinol(Lausanne), 2019, 10: 603.

    [49] SHI J, GAO W, SHAO F. Pyroptosis: gasdermin-mediated programmed necrotic cell death [J]. Trends Biochem Sci, 2017, 42 (4): 24.

    [50] WANG S, YUAN Y H, CHEN N H, et al. The mechanisms of NLRP3 inflammasome /pyroptosis activation and their role in Parkinson’s disease [J]. Int Immunopharmacol, 2019, 67: 458.

    [51] Miyake S, Shindou R, Nakano H. ネクロプトーシス,フェロトーシス,パイロトーシスの分子機構と生体内における機能 [J]. Clinical Calcium, 2019, 29 (2): 248 (in Japanese).

    [52] WU W, LIU B H, WAN Y G. Ermiao Pill improves podocyte pyroptosis in diabetic kidney disease by targeting HIF-1α-mediated NLRP3/GSDMD pathway [C]. Yokohama: the 63rd annual meeting of the Japanese society of nephropathy (JSN), 2020.

This Article

ISSN:1001-5302

CN: 11-2272/R

Vol 45, No. 20, Pages 4805-4811

October 2020

Downloads:2

Share
Article Outline

Abstract

  • 1 Structures, functions, and degradation of HIFs
  • 2 Molecular regulation mechanism of HIF-1α
  • 3 HIF-1α and inflammatory response as well as intervention with Chinese herbal medicines
  • 4 HIF-1α and autophagy as well as intervention with Chinese herbal medicine
  • 5 HIF-1α and epigenetic modification as well as intervention with Chinese herbal medicine
  • 6 HIF-1α and pyroptosis as well as intervention with Chinese herbal medicine
  • References