Vol 55, No 3 (2017)
Original paper
Published online: 2017-09-19

open access

Page views 2019
Article views/downloads 1793
Get Citation

Connect on Social Media

Connect on Social Media

Repression of the Notch pathway prevents liver damage in streptozotocin-induced diabetic mice

Eda Acikgoz, Huseyin Aktug, Gurkan Yigitturk, Kenan Demir, Ummu Guven, Fahriye Duzagac, Fatih Oltulu1, Altug Yavasoglu, Gulperi Oktem
Pubmed: 28994095
Folia Histochem Cytobiol 2017;55(3):140-148.


Introduction. Sunitinib is an oral inhibitor of vascular endothelial growth factor that is used to treat a variety of cancer. There are limited data regarding the effect of sunitinib on diabetes. In the liver, Notch signaling plays an important role in liver tissue development and homeostasis and its dysfunction is associated with liver pathol­ogies. The aim of the present study is to investigate the effects of sunitinib on streptozotocin (STZ)-induced diabetic liver in mice models.

Material and methods. An experimental diabetes mellitus (DM) model was created in 28 male CD-1 mice. Twenty-eight male CD-1 mice divided in four groups (n = 7 each) were used; control mice (C), control mice treated with sunitinib (C + S), diabetic mice (DM), and diabetic mice treated with sunitinib (DM + S) for four weeks. The histopathological changes in the liver were examined by histochemistry and immunohistochemistry. Immunoreactivity of Notch1, Jagged1, DLL-1 and VEGF were evaluated in control and diabetic mice after sunitinib treatment.

Results. The significant morphological changes in the liver were mostly seen in hepatocytes that were hyper­trophied in the DM mice, with an increased amount of eosinophilic granules; moreover, some hepatocytes contained empty vacuole-like structures. The livers of the DM mice revealed increased deposition of collagen fibers. After sunitinib treatment the hepatocytes and hepatic lobules had almost similar morphology to control mice. The immunoreactivities of Notch1, Jagged1, DLL-1 and VEGF in hepatocytes were significantly lower in the DM group when compared with the C, DM + S and C + S group treated with sunitinib.

Conclusions. These results suggest that sunitinib effectively protects the liver from diabetes-induced damage through the inhibition of the Notch pathway.

Article available in PDF format

View PDF Download PDF file


  1. Patterson CC, Dahlquist GG, Gyürüs E, et al. EURODIAB Study Group. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet. 2009; 373(9680): 2027–2033.
  2. van Belle TL, Coppieters KT, von Herrath MG. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev. 2011; 91(1): 79–118.
  3. Perkins BA, Bril V. Emerging therapies for diabetic neuropathy: a clinical overview. Curr Diabetes Rev. 2005; 1(3): 271–280.
  4. Jain SK, McVie R, Bocchini JA. Hyperketonemia (ketosis), oxidative stress and type 1 diabetes. Pathophysiology. 2006; 13(3): 163–170.
  5. Ohno T, Horio F, Tanaka S, et al. Fatty liver and hyperlipidemia in IDDM (insulin-dependent diabetes mellitus) of streptozotocin-treated shrews. Life Sci. 2000; 66(2): 125–131.
  6. Al-Hussaini AA, Sulaiman NM, Alzahrani MD, et al. Prevalence of hepatopathy in type 1 diabetic children. BMC Pediatr. 2012; 12: 160.
  7. Takamatsu S, Noguchi N, Kudoh A, et al. Influence of risk factors for metabolic syndrome and non-alcoholic fatty liver disease on the progression and prognosis of hepatocellular carcinoma. Hepatogastroenterology. 2008; 55(82-83): 609–614.
  8. Inoue M, Iwasaki M, Otani T, et al. Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. Arch Intern Med. 2006; 166(17): 1871–1877.
  9. Wang C, Wang X, Gong G, et al. Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. Int J Cancer. 2012; 130(7): 1639–1648.
  10. Hägerkvist R, Sandler S, Mokhtari D, et al. Amelioration of diabetes by imatinib mesylate (Gleevec): role of beta-cell NF-kappaB activation and anti-apoptotic preconditioning. FASEB J. 2007; 21(2): 618–628.
  11. Louvet C, Szot GL, Lang J, et al. Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci USA. 2008; 105(48): 18895–18900.
  12. Little PJ, Cohen N, Morahan G. Potential of small molecule protein tyrosine kinase inhibitors as immuno-modulators and inhibitors of the development of type 1 diabetes. ScientificWorldJournal. 2009; 9: 224–228.
  13. Mokhtari D, Welsh N. Potential utility of small tyrosine kinase inhibitors in the treatment of diabetes. Clin Sci (Lond). 2009; 118(4): 241–247.
  14. Abrams TJ, Lee LB, Murray LJ, et al. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003; 2(5): 471–478.
  15. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003; 9(1): 327–337.
  16. Agostino NM, Chinchilli VM, Lynch CJ, et al. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice. J Oncol Pharm Pract. 2011; 17(3): 197–202.
  17. Templeton A, Brändle M, Cerny T, et al. Remission of diabetes while on sunitinib treatment for renal cell carcinoma. Ann Oncol. 2008; 19(4): 824–825.
  18. Bi P, Kuang S. Notch signaling as a novel regulator of metabolism. Trends Endocrinol Metab. 2015; 26(5): 248–255.
  19. Tremolada G, Lattanzio R, Mazzolari G, et al. The therapeutic potential of VEGF inhibition in diabetic microvascular complications. Am J Cardiovasc Drugs. 2007; 7(6): 393–398.
  20. Lin CL, Wang FS, Hsu YC, et al. Modulation of notch-1 signaling alleviates vascular endothelial growth factor-mediated diabetic nephropathy. Diabetes. 2010; 59(8): 1915–1925.
  21. Sönmez MF, Karabulut D, Kilic E, et al. The effects of streptozotocin-induced diabetes on ghrelin expression in rat testis: biochemical and immunohistochemical study. Folia Histochem Cytobiol. 2015; 53(1): 26–34.
  22. Ayuob NN, Murad HAS, Ali SS. Impaired expression of sex hormone receptors in male reproductive organs of diabetic rat in response to oral antidiabetic drugs. Folia Histochem Cytobiol. 2015; 53(1): 35–48.
  23. Laguens RP, Candela S, Hernández RE, et al. Streptozotocin-induced liver damage in mice. Horm Metab Res. 1980; 12(5): 197–201.
  24. Afrin R, Arumugam S, Soetikno V, et al. Curcumin ameliorates streptozotocin-induced liver damage through modulation of endoplasmic reticulum stress-mediated apoptosis in diabetic rats. Free Radic Res. 2015; 49(3): 279–289.
  25. Oršolić N, Sirovina D, Končić MZ, et al. Effect of Croatian propolis on diabetic nephropathy and liver toxicity in mice. BMC Complement Altern Med. 2012; 12: 117.
  26. de Cavanagh EM, Inserra F, Toblli J, et al. Enalapril attenuates oxidative stress in diabetic rats. Hypertension. 2001; 38(5): 1130–1136.
  27. Lutz SZ, Ullrich A, Häring HU, et al. Sunitinib specifically augments glucose-induced insulin secretion. Cell Signal. 2017; 36: 91–97.
  28. Morell CM, Strazzabosco M. Notch signaling and new therapeutic options in liver disease. J Hepatol. 2014; 60(4): 885–890.
  29. Geisler F, Strazzabosco M. Emerging roles of Notch signaling in liver disease. Hepatology. 2015; 61(1): 382–392.
  30. Valenti L, Mendoza RM, Rametta R, et al. Hepatic notch signaling correlates with insulin resistance and nonalcoholic fatty liver disease. Diabetes. 2013; 62(12): 4052–4062.
  31. Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol. 2006; 24(1): 25–35.
  32. Thomas JL, Baker K, Han J, et al. Interactions between VEGFR and Notch signaling pathways in endothelial and neural cells. Cell Mol Life Sci. 2013; 70(10): 1779–1792.
  33. Sawitza I, Kordes C, Reister S, et al. The niche of stellate cells within rat liver. Hepatology. 2009; 50(5): 1617–1624.
  34. Chen Y, Zheng S, Qi D, et al. Inhibition of Notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats. PLoS One. 2012; 7(10): e46512.
  35. Tugues S, Fernandez-Varo G, Muñoz-Luque J, et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology. 2007; 46(6): 1919–1926.
  36. Elsner A, Lange F, Fitzner B, et al. Distinct antifibrogenic effects of erlotinib, sunitinib and sorafenib on rat pancreatic stellate cells. World J Gastroenterol. 2014; 20(24): 7914–7925.
  37. Stockhausen MT, Sjölund J, Axelson H. Regulation of the Notch target gene Hes-1 by TGFalpha induced Ras/MAPK signaling in human neuroblastoma cells. Exp Cell Res. 2005; 310(1): 218–228.
  38. Papaetis GS, Syrigos KN. Sunitinib: a multitargeted receptor tyrosine kinase inhibitor in the era of molecular cancer therapies. BioDrugs. 2009; 23(6): 377–389.
  39. Shibuya M. VEGFR and type-V RTK activation and signaling. Cold Spring Harb Perspect Biol. 2013; 5(10): a009092.
  40. Cébe-Suarez S, Zehnder-Fjällman A, Ballmer-Hofer K. The role of VEGF receptors in angiogenesis; complex partnerships. Cell Mol Life Sci. 2006; 63(5): 601–615.
  41. Yang L, Kwon J, Popov Y, et al. Vascular endothelial growth factor promotes fibrosis resolution and repair in mice. Gastroenterology. 2014; 146(5): 1339–13350.e1.
  42. Duyndam MCA, Hilhorst MC, Schlüper HMM, et al. Vascular endothelial growth factor-165 overexpression stimulates angiogenesis and induces cyst formation and macrophage infiltration in human ovarian cancer xenografts. Am J Pathol. 2002; 160(2): 537–548.
  43. Hagberg CE, Mehlem A, Falkevall A, et al. Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature. 2012; 490(7420): 426–430.
  44. Villalta SA, Lang J, Kubeck S, et al. Inhibition of VEGFR-2 reverses type 1 diabetes in NOD mice by abrogating insulitis and restoring islet function. Diabetes. 2013; 62(8): 2870–2878.
  45. Cha DR, Kim NH, Yoon JW, et al. Role of vascular endothelial growth factor in diabetic nephropathy. Kidney Int Suppl. 2000; 77: S104–S112.
  46. Tsai CH, Chiang YC, Chen HT, et al. High glucose induces vascular endothelial growth factor production in human synovial fibroblasts through reactive oxygen species generation. Biochim Biophys Acta. 2013; 1830(3): 2649–2658.
  47. Brahimi-Horn MC, Pouysségur J. Harnessing the hypoxia-inducible factor in cancer and ischemic disease. Biochem Pharmacol. 2007; 73(3): 450–457.
  48. Xiao H, Gu Z, Wang G, et al. The possible mechanisms underlying the impairment of HIF-1α pathway signaling in hyperglycemia and the beneficial effects of certain therapies. Int J Med Sci. 2013; 10(10): 1412–1421.
  49. Yan J, Zhang Z, Shi H. HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells. Cell Mol Life Sci. 2012; 69(1): 115–128.
  50. Haligur M, Topsakal S, Ozmen O. Early degenerative effects of diabetes mellitus on pancreas, liver, and kidney in rats: an immunohistochemical study. Exp Diabetes Res. 2012; 2012: 1–10.