Ukr.Biochem.J. 2023; Volume 95, Issue 6, Nov-Dec, pp. 40-49

doi: https://doi.org/10.15407/ubj95.06.040

Phenobarbital ameliorates hyperglycemia-induced angiogenesis in diabetic nephropathy-possible intervention at the HIF-1α/VEGF axis

11.12.2023   Uncategorized   No comments

M. M. Mohammed1*, S. R. A. Rehim1, A. M. M. Okasha1, H. El-Mezayen2,
D. G. A. N. Mohammed2, W. Gomaa3, F. Mourad4, E. G. Ayad2

1Department of Biochemistry, Faculty of Medicine, Minia University, El-Minia, Egypt;
2Department of Chemistry, Faculty of Science, Helwan University, Helwan, Egypt;
3Department of Pathology, Faculty of Medicine, Minia University, El-Minia, Egypt;
4MSP, Faculty of Pharmacy, Deraya University, El-Minia, Egypt;
*e-mail: mostafa.mohamed@mu.edu.eg

Received: 17 September 2023; Revised: 17 November 2023;
Accepted: 01 December 2023; Available on-line: 18 December 2023

Hyperglycemia contributes to a cascade of inflammatory responses in kidneys that result in the development of renal hypoxia and angiogenesis with subsequent chronic renal failure. As the hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) axis is a key pathway for neovascularization, the inhibition of this axis is a target for renal angiogenesis therapy. We speculate that Phenobarbital (PB) which has a potential to reduce vascularization in clinical settings might have an influence on the development of angiogenesis in diabetic kidney. The aim of the study was to explore the effects of PB on the HIF-1α and VEGF expression and angiogenesis in renal tissue of rats with hyperglycemia and diabetic nephropathy. Sixty-four male Wistar rats were devided into 4 groups: control group received a single intraperitoneal saline injection; PB group received 0.05% PB orally in drinking water; diabetic group received a single intra-peritoneal STZ (65 mg/kg) injection; PB-STZ group received 0.05% PB orally two weeks before STZ administration. At the end of the experiment period (8 weeks), the kidneys were removed and used for biochemical analyses. Serum glucose, urea and creatinine levels, IL-6 levels in kidney homogenate and changes in HIF-1α and VEGF gene expression were estimated. Hematoxylin-eosin staining was performed for histopathological exa­mination. The results obtained showed that both HIF-1α and VEGF gene expression and IL6 level in diabetic rat group were significantly elevated compared to that in control group, whereas in PB and PB-STZ groups, these indices were significantly down-regulated compared to the diabetic group. Abundant glomerular congestion and mesangial proliferation were detected in diabetic rat renal tissues. However, in PB-treated diabetic group, newly formed vessels were significantly decreased. These findings confirmed that phenobarbital, affecting the HIF-1α/VEGF signaling pathway, ameliorates angiogenesis after hyperglycemic kidney injury.

Keywords: , , , , ,

References:

  1. Fu Z, Chen D, Cheng H, Wang F. Hypoxia-inducible factor-1α protects cervical carcinoma cells from apoptosis induced by radiation via modulation of vascular endothelial growth factor and p53 under hypoxia. Med Sci Monit. 2015;21:318-325. PubMed, PubMedCentral, CrossRef
  2. Lou Z, Li Q, Wang C, Li Y. The effects of microRNA-126 reduced inflammation and apoptosis of diabetic nephropathy through PI3K/AKT signalling pathway by VEGF. Arch Physiol Biochem. 2022;128(5):1265-1274. PubMed, CrossRef
  3. Borgohain MP, Lahkar M, Ahmed S, Chowdhury L, Kumar S, Pant R, Choubey A. Small Molecule Inhibiting Nuclear Factor-kB Ameliorates Oxidative Stress and Suppresses Renal Inflammation in Early Stage of Alloxan-Induced Diabetic Nephropathy in Rat. Basic Clin Pharmacol Toxicol. 2017;120(5):442-449. PubMed, CrossRef
  4. Ahmed MA, Alzokaky AA, Raslan NA, Abdelbaky NA. Comparative study on the influence of L carnitine and/or fenofibrate against streptozotocin induced diabetic nephropathy: role of TGFβ1/Smad Signaling Pathway. Azhar Int J Pharm Med Sci. 2022;2(1):48-57. CrossRef
  5. DCCT/EDIC Research Group, de Boer IH, Sun W, Cleary PA, Lachin JM, Molitch ME, Steffes MW, Zinman B. Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. N Engl J Med. 2011;365(25):2366-2376. PubMed, PubMedCentral, CrossRef
  6. Ichinose K, Maeshima Y, Yamamoto Y, Kitayama H, Takazawa Y, Hirokoshi K, Sugiyama H, Yamasaki Y, Eguchi K, Makino H. Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model. Diabetes. 2005;54(10):2891-2903. PubMed, CrossRef
  7. Yamamoto Y, Maeshima Y, Kitayama H, Kitamura S, Takazawa Y, Sugiyama H, Yamasaki Y, Makino H. Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy. Diabetes. 2004;53(7):1831-1840. PubMed, CrossRef
  8. Pourshabanan P, Momeni A, Mahmoudnia L, Kheiri S. Effect of pioglitazone on decreasing of proteinuria in type 2 diabetic patients with nephropathy. Diabetes Metab Syndr. 2019;13(1):132-136. PubMed, CrossRef
  9. Declèves AE, Mathew AV, Cunard R, Sharma K. AMPK mediates the initiation of kidney disease induced by a high-fat diet. J Am Soc Nephrol. 2011;22(10):1846-1855. PubMed, PubMedCentral, CrossRef
  10. Zhang X, Ma L, Dong H, Lv Z, Liu Y, Gao J, Wang R. Effect of HIF-1α, VEGF and MVD expression on angiogenesis in diabetic nephropathy. Int J Clin Exp Med. 2018;11(2):1247-1253.
  11. Xu Y, Kong X, Li J, Cui T, Wei Y, Xu J, Zhu Y, Zhu X. Mild Hypoxia Enhances the Expression of HIF and VEGF and Triggers the Response to Injury in Rat Kidneys. Front Physiol. 2021;12:690496. PubMed, PubMedCentral, CrossRef
  12. Yang K, Zhang Z, Li Y, Chen S, Chen W, Ding H, Tan Z, Ma Z, Qiao Z. Expression and distribution of HIF-1α, HIF-2α, VEGF, VEGFR-2 and HIMF in the kidneys of Tibetan sheep, plain sheep and goat. Folia Morphol (Warsz). 2020;79(4):748-755. PubMed, CrossRef
  13. Kazmi Z, Zeeshan S, Khan A, Malik S, Shehzad A, Seo EK, Khan S. Anti-epileptic activity of daidzin in PTZ-induced mice model by targeting oxidative stress and BDNF/VEGF signaling. Neurotoxicology. 2020;79:150-163. PubMed, CrossRef
  14. Yan Y, Cheng X, Yang RH, Li H, Chen JL, Ma ZL, Wang G, Chuai M, Yang X. Exposure to Excess Phenobarbital Negatively Influences the Osteogenesis of Chick Embryos. Front Pharmacol. 2016;7:349. PubMed, PubMedCentral, CrossRef
  15. Lowe SA. Drugs in pregnancy. Anticonvulsants and drugs for neurological disease. Best Pract Res Clin Obstet Gynaecol. 2001;15(6):863-876. PubMed, CrossRef
  16. Furman BL. Streptozotocin-Induced Diabetic Models in Mice and Rats. Curr Protoc Pharmacol. 2015;70:5.47.1-5.47.20. PubMed, CrossRef
  17. Holsapple MP, Pitot HC, Cohen SM, Boobis AR, Klaunig JE, Pastoor T, Dellarco VL, Dragan YP. Mode of action in relevance of rodent liver tumors to human cancer risk. Toxicol Sci. 2006;89(1):51-56. PubMed, CrossRef
  18. VanGuilder HD, Vrana KE, Freeman WM. Twenty-five years of quantitative PCR for gene expression analysis. Biotechniques. 2008;44(5):619-626.
    PubMed,CrossRef
  19. Introductory Chapter: Histological Microtechniques. Eds. Shields VD, Heinbockel T. In: Histology. 2018, IntechOpen. 148 p. CrossRef
  20. Zhang D, Lv FL, Wang GH. Effects of HIF-1α on diabetic retinopathy angiogenesis and VEGF expression. Eur Rev Med Pharmacol Sci. 2018;22(16):5071-5076. PubMed, CrossRef
  21. Cha DR, Kim NH, Yoon JW, Jo SK, Cho WY, Kim HK, Won NH. Role of vascular endothelial growth factor in diabetic nephropathy. Kidney Int Suppl. 2000;77:S104-S112. PubMed, CrossRef
  22. Araldi E, Schipani E. Hypoxia, HIFs and bone development. Bone. 2010;47(2):190-196. PubMed, PubMedCentral, CrossRef
  23. Araújo LS, Torquato BGS, da Silva CA, Dos Reis Monteiro MLG, Dos Santos Martins ALM, da Silva MV, Dos Reis MA, Machado JR. Renal expression of cytokines and chemokines in diabetic nephropathy. BMC Nephrol. 2020;21(1):308. PubMed, PubMedCentral, CrossRef
  24. Catar R, Witowski J, Zhu N, Lücht C, Derrac Soria A, Uceda Fernandez J, Chen L, Jones SA, Fielding CA, Rudolf A, Topley N, Dragun D, Jörres A. IL-6 Trans-Signaling Links Inflammation with Angiogenesis in the Peritoneal Membrane. J Am Soc Nephrol. 2017;28(4):1188-1199. PubMed, PubMedCentral, CrossRef
  25. Klemis V, Ghura H, Federico G, Würfel C, Bentmann A, Gretz N, Miyazaki T, Gröne HJ, Nakchbandi IA. Circulating fibronectin contributes to mesangial expansion in a murine model of type 1 diabetes. Kidney Int. 2017;91(6):1374-1385. PubMed, CrossRef
  26. Baccora MHA, Cortes P, Hassett C, Taube DW, Yee J. Effects of long-term elevated glucose on collagen formation by mesangial cells. Kidney Int. 2007;72(10):1216-1225. PubMed, CrossRef
  27. Young BA, Johnson RJ, Alpers CE, Eng E, Gordon K, Floege J, Couser WG, Seidel K. Cellular events in the evolution of experimental diabetic nephropathy. Kidney Int. 1995;47(3):935-944. PubMed, CrossRef
  28. Liu H, Feng J, Tang L. Early renal structural changes and potential biomarkers in diabetic nephropathy. Front Physiol. 2022;13:1020443. PubMed, PubMedCentral, CrossRef
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