Lack of HB-EGF Expression is Protective against Chronic Kidney Disease under Diabetic Conditions
Main Article Content
Abstract
Chronic kidney disease affects about 1 out of 3 adults with diabetes that may result in kidney failure and possibly end-stage renal disease. The aim of this study is to determine the role of HB-EGF as a contributing factor to chronic kidney disease in streptozotocin induced diabetic mice. We find that streptozotocin-induced diabetic wild-type, human HB-EGF transgenic, HB-EGF heterozygous, and HB-EGF null mice resulted in hyperglycemic conditions compared to control mice, exhibited enlarged kidney size, weight, and glomerular cross-sectional area and were directly correlated to the levels of HB-EGF. Collagen formation was was observed in the kidneys of wild type, heterozygous, and transgenic streptozotocin-mice but absent in HB-EGF -/- as well as control mice suggesting that HB-EGF stimulates fibrosis. Serum insulin like growth factor-1 and insulin like growth factor binding protein-3 levels in streptozotocin-diabetic HB-EGF transgenic were significantly higher indicating HB-EGF may be contributing to chronic kidney disease. Collectively, these findings suggest that the lack of HB-EGF may be protective against steptozotocin-induced chronic kidney disease.
Keywords:
HB-EGF, transgenic, streptozotocin, diabetic kidney disease
Article Details
How to Cite
S. R., Taylor et al.
Lack of HB-EGF Expression is Protective against Chronic Kidney Disease under Diabetic Conditions.
Medical Research Archives, [S.l.], v. 13, n. 7, july 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6710>. Date accessed: 05 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i7.6710.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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4. Melenhorst WB, Mulder GM, Xi Q, et al. Epidermal growth factor receptor signaling in the kidney: key roles in physiology and disease. Hypertension. 2008;52(6):987-993. doi:10.1161/HYPERTENSIONAHA.108.113860
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8. Homma T, Sakai M, Cheng HF, Yasuda T, Coffey RJ Jr, Harris RC. Induction of heparin-binding epidermal growth factor-like growth factor mRNA in rat kidney after acute injury. J Clin Invest. 1995;96(2):1018-1025. doi:10.1172/JCI118087
9. Sakai M, Zhang M, Homma T, et al. Production of heparin binding epidermal growth factor-like growth factor in the early phase of regeneration after acute renal injury. Isolation and localization of bioactive molecules. J Clin Invest. 1997;99(9):2128-2138. doi:10.1172/JCI119386
10. Higashiyama S, Abraham JA, Miller J, Fiddes JC, Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science. 1991;251(4996):936-939. doi:10.1126/science.1840698
11. Higashiyama S, Lau K, Besner GE, Abraham JA, Klagsbrun M. Structure of heparin-binding EGF-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein. J Biol Chem. 1992;267(9):6205-6212.
12. Higashiyama S, Abraham JA, Klagsbrun M. Heparin-binding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate. J Cell Biol. 1993;122(4):933-940. doi:10.1083/jcb.122.4.933
13. Ito N, Kawata S, Tamura S, et al. Heparin-binding EGF-like growth factor is a potent mitogen for rat hepatocytes [published correction appears in Biochem Biophys Res Commun 1994 Mar 15;199(2):1088]. Biochem Biophys Res Commun. 1994;198(1):25-31. doi:10.1006/bbrc.1994.1004
14. Oh Y. The insulin-like growth factor system in chronic kidney disease: Pathophysiology and therapeutic opportunities. Kidney Res Clin Pract. 2012;31(1):26-37. doi:10.1016/j.krcp.2011.12.005
15. Kanwar YS, Wada J, Sun L, et al. Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med (Maywood). 2008;233(1):4-11. doi:10.3181/0705-MR-134
16. Reddy AS. (2004) Diabetic nephropathy: theory & practice. East Hanover.
17. Provenzano AP, Besner GE, James PF, Harding PA. Heparin-binding EGF-like growth factor (HB-EGF) overexpression in transgenic mice downregulates insulin-like growth factor binding protein (IGFBP)-3 and -4 mRNA. Growth Factors. 2005;23(1):19-31. doi:10.1080/08977140512331344012
18. Jackson LF, Qiu TH, Sunnarborg SW, et al. Defective valvulogenesis in HB-EGF and TACE-null mice is associated with aberrant BMP signaling. EMBO J. 2003;22(11):2704-2716. doi:10.1093/emboj/cdg264
19. Zerbini G, Gabellini D, Maestroni S, Maestroni A. Early renal dysfunctions in type 1 diabetes and pathogenesis of diabetic nephropathy. J Nephrol. 2007;20 Suppl 12:S19-S22.
20. Colquhoun DR, Goldman LR, Cole RN, et al. Global screening of human cord blood proteomes for biomarkers of toxic exposure and effect. Environ Health Perspect. 2009;117(5):832-838. doi:10.1289/ehp.11816
21. Zeid AM, Lamontagne JO, Zhang H, Marneros AG. Epidermal growth factor deficiency predisposes to progressive renal disease. FASEB J. 2022;36(5):e22286. doi:10.1096/fj.202101837R
22. Besner G, Higashiyama S, Klagsbrun M. Isolation and characterization of a macrophage-derived heparin-binding growth factor. Cell Regul. 1990;1(11):811-819. doi:10.1091/mbc.1.11.811
23. Kiso S, Kawata S, Tamura S, et al. Liver regeneration in heparin-binding EGF-like growth factor transgenic mice after partial hepatectomy. Gastroenterology. 2003;124(3):701-707. doi:10.1053/gast.2003.50097
24. Means AL, Ray KC, Singh AB, et al. Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia. Gastroenterology. 2003;124(4):1020-1036. doi:10.1053/gast.2003.50150
25. Iwamoto R, Yamazaki S, Asakura M, et al. Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc Natl Acad Sci U S A. 2003;100(6):3221-3226. doi:10.1073/pnas.0537588100
26. Naglich JG, Metherall JE, Russell DW, Eidels L. Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell. 1992;69(6):1051-1061. doi:10.1016/0092-8674(92)90623-k
27. Nakagawa T, Higashiyama S, Mitamura T, Mekada E, Taniguchi N. Amino-terminal processing of cell surface heparin-binding epidermal growth factor-like growth factor up-regulates its juxtacrine but not its paracrine growth factor activity. J Biol Chem. 1996;271(48):30858-30863. doi:10.1074/jbc.271.48.30858
28. Asakura M, Kitakaze M, Takashima S, et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nat Med. 2002;8(1):35-40. doi:10.1038/nm0102-35
29. Nanba D, Toki F, Higashiyama S. Roles of charged amino acid residues in the cytoplasmic domain of proHB-EGF. Biochem Biophys Res Commun. 2004;320(2):376-382. doi:10.1016/j.bbrc.2004.05.176
30. Goishi K, Higashiyama S, Klagsbrun M, et al. Phorbol ester induces the rapid processing of cell surface heparin-binding EGF-like growth factor: conversion from juxtacrine to paracrine growth factor activity. Mol Biol Cell. 1995;6(8):967-980. doi:10.1091/mbc.6.8.967
31. Gechtman Z, Alonso JL, Raab G, Ingber DE, Klagsbrun M. The shedding of membrane-anchored heparin-binding epidermal-like growth factor is regulated by the Raf/mitogen-activated protein kinase cascade and by cell adhesion and spreading. J Biol Chem. 1999;274(40):28828-28835. doi:10.1074/jbc.274.40.28828
32. Schaefer F and Rabkin R (2003) Insulin-like growth factor and the kidney. In: LeRoith D., Zumkeller W., Baxter R.C., editors. Insulin-like Growth Factors. Kluwer Academic/Plenum Publishers; New York: 2003. pp. 244–255.
33. Roelfsema V, Clark RG. The growth hormone and insulin-like growth factor axis: its manipulation for the benefit of growth disorders in renal failure. J Am Soc Nephrol. 2001;12(6):1297-1306. doi:10.1681/ASN.V1261297
34. Hirschberg R, Adler S. Insulin-like growth factor system and the kidney: physiology, pathophysiology, and therapeutic implications. Am J Kidney Dis. 1998;31(6):901-919. doi:10.1053/ajkd.1998.v31.pm9631833
35. Mathews LS, Hammer RE, Behringer RR, et al. Growth enhancement of transgenic mice expressing human insulin-like growth factor I. Endocrinology. 1988;123(6):2827-2833. doi:10.1210/endo-123-6-2827
36. Quaife CJ, Mathews LS, Pinkert CA, Hammer RE, Brinster RL, Palmiter RD. Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice. Endocrinology. 1989;124(1):40-48. doi:10.1210/endo-124-1-40
37. Doi T, Striker LJ, Gibson CC, Agodoa LY, Brinster RL, Striker GE. Glomerular lesions in mice transgenic for growth hormone and insulinlike growth factor-I. I. Relationship between increased glomerular size and mesangial sclerosis. Am J Pathol. 1990;137(3):541-552.
38. Franklin SC, Moulton M, Sicard GA, Hammerman MR, Miller SB. Insulin-like growth factor I preserves renal function postoperatively. Am J Physiol. 1997;272(2 Pt 2):F257-F259. doi:10.1152/ajprenal.1997.272.2.F257
39. Vijayan A, Franklin SC, Behrend T, Hammerman MR, Miller SB. Insulin-like growth factor I improves renal function in patients with end-stage chronic renal failure. Am J Physiol. 1999;276(4):R929-R934. doi:10.1152/ajpregu.1999.276.4.R929
40. Hammerman MR, Miller SB. Effects of growth hormone and insulin-like growth factor I on renal growth and function. J Pediatr. 1997;131(1 Pt 2):S17-S19. doi:10.1016/s0022-3476(97)70004-0
41. O'Shea MH, Miller SB, Hammerman MR. Effects of IGF-I on renal function in patients with chronic renal failure. Am J Physiol. 1993;264(5 Pt 2):F917-F922. doi:10.1152/ajprenal.1993.264.5.F917
2. Daher A, de Boer WI, El-Marjou A, et al. Epidermal growth factor receptor regulates normal urothelial regeneration. Lab Invest. 2003;83(9):1333-1341. doi:10.1097/01.lab.0000086380.23263.52
3. Raab G, Klagsbrun M. Heparin-binding EGF-like growth factor. Biochim Biophys Acta. 1997;1333(3):F179-F199. doi:10.1016/s0304-419x(97)00024-3
4. Melenhorst WB, Mulder GM, Xi Q, et al. Epidermal growth factor receptor signaling in the kidney: key roles in physiology and disease. Hypertension. 2008;52(6):987-993. doi:10.1161/HYPERTENSIONAHA.108.113860
5. Cao S, Pan Y, Terker AS, et al. Epidermal growth factor receptor activation is essential for kidney fibrosis development. Nat Commun. 2023;14(1):7357. Published 2023 Nov 14. doi:10.1038/s41467-023-43226-x
6. Abraham JA, Damm D, Bajardi A, Miller J, Klagsbrun M, Ezekowitz RA. Heparin-binding EGF-like growth factor: characterization of rat and mouse cDNA clones, protein domain conservation across species, and transcript expression in tissues. Biochem Biophys Res Commun. 1993;190(1):125-133. doi:10.1006/bbrc.1993.1020
7. Lee YJ, Shin SJ, Lin SR, Tan MS, Tsai JH. Increased expression of heparin binding epidermal growth-factor-like growth factor mRNA in the kidney of streptozotocin-induced diabetic rats. Biochem Biophys Res Commun. 1995;207(1):216-222. doi:10.1006/bbrc.1995.1175
8. Homma T, Sakai M, Cheng HF, Yasuda T, Coffey RJ Jr, Harris RC. Induction of heparin-binding epidermal growth factor-like growth factor mRNA in rat kidney after acute injury. J Clin Invest. 1995;96(2):1018-1025. doi:10.1172/JCI118087
9. Sakai M, Zhang M, Homma T, et al. Production of heparin binding epidermal growth factor-like growth factor in the early phase of regeneration after acute renal injury. Isolation and localization of bioactive molecules. J Clin Invest. 1997;99(9):2128-2138. doi:10.1172/JCI119386
10. Higashiyama S, Abraham JA, Miller J, Fiddes JC, Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science. 1991;251(4996):936-939. doi:10.1126/science.1840698
11. Higashiyama S, Lau K, Besner GE, Abraham JA, Klagsbrun M. Structure of heparin-binding EGF-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein. J Biol Chem. 1992;267(9):6205-6212.
12. Higashiyama S, Abraham JA, Klagsbrun M. Heparin-binding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate. J Cell Biol. 1993;122(4):933-940. doi:10.1083/jcb.122.4.933
13. Ito N, Kawata S, Tamura S, et al. Heparin-binding EGF-like growth factor is a potent mitogen for rat hepatocytes [published correction appears in Biochem Biophys Res Commun 1994 Mar 15;199(2):1088]. Biochem Biophys Res Commun. 1994;198(1):25-31. doi:10.1006/bbrc.1994.1004
14. Oh Y. The insulin-like growth factor system in chronic kidney disease: Pathophysiology and therapeutic opportunities. Kidney Res Clin Pract. 2012;31(1):26-37. doi:10.1016/j.krcp.2011.12.005
15. Kanwar YS, Wada J, Sun L, et al. Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med (Maywood). 2008;233(1):4-11. doi:10.3181/0705-MR-134
16. Reddy AS. (2004) Diabetic nephropathy: theory & practice. East Hanover.
17. Provenzano AP, Besner GE, James PF, Harding PA. Heparin-binding EGF-like growth factor (HB-EGF) overexpression in transgenic mice downregulates insulin-like growth factor binding protein (IGFBP)-3 and -4 mRNA. Growth Factors. 2005;23(1):19-31. doi:10.1080/08977140512331344012
18. Jackson LF, Qiu TH, Sunnarborg SW, et al. Defective valvulogenesis in HB-EGF and TACE-null mice is associated with aberrant BMP signaling. EMBO J. 2003;22(11):2704-2716. doi:10.1093/emboj/cdg264
19. Zerbini G, Gabellini D, Maestroni S, Maestroni A. Early renal dysfunctions in type 1 diabetes and pathogenesis of diabetic nephropathy. J Nephrol. 2007;20 Suppl 12:S19-S22.
20. Colquhoun DR, Goldman LR, Cole RN, et al. Global screening of human cord blood proteomes for biomarkers of toxic exposure and effect. Environ Health Perspect. 2009;117(5):832-838. doi:10.1289/ehp.11816
21. Zeid AM, Lamontagne JO, Zhang H, Marneros AG. Epidermal growth factor deficiency predisposes to progressive renal disease. FASEB J. 2022;36(5):e22286. doi:10.1096/fj.202101837R
22. Besner G, Higashiyama S, Klagsbrun M. Isolation and characterization of a macrophage-derived heparin-binding growth factor. Cell Regul. 1990;1(11):811-819. doi:10.1091/mbc.1.11.811
23. Kiso S, Kawata S, Tamura S, et al. Liver regeneration in heparin-binding EGF-like growth factor transgenic mice after partial hepatectomy. Gastroenterology. 2003;124(3):701-707. doi:10.1053/gast.2003.50097
24. Means AL, Ray KC, Singh AB, et al. Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia. Gastroenterology. 2003;124(4):1020-1036. doi:10.1053/gast.2003.50150
25. Iwamoto R, Yamazaki S, Asakura M, et al. Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc Natl Acad Sci U S A. 2003;100(6):3221-3226. doi:10.1073/pnas.0537588100
26. Naglich JG, Metherall JE, Russell DW, Eidels L. Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell. 1992;69(6):1051-1061. doi:10.1016/0092-8674(92)90623-k
27. Nakagawa T, Higashiyama S, Mitamura T, Mekada E, Taniguchi N. Amino-terminal processing of cell surface heparin-binding epidermal growth factor-like growth factor up-regulates its juxtacrine but not its paracrine growth factor activity. J Biol Chem. 1996;271(48):30858-30863. doi:10.1074/jbc.271.48.30858
28. Asakura M, Kitakaze M, Takashima S, et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nat Med. 2002;8(1):35-40. doi:10.1038/nm0102-35
29. Nanba D, Toki F, Higashiyama S. Roles of charged amino acid residues in the cytoplasmic domain of proHB-EGF. Biochem Biophys Res Commun. 2004;320(2):376-382. doi:10.1016/j.bbrc.2004.05.176
30. Goishi K, Higashiyama S, Klagsbrun M, et al. Phorbol ester induces the rapid processing of cell surface heparin-binding EGF-like growth factor: conversion from juxtacrine to paracrine growth factor activity. Mol Biol Cell. 1995;6(8):967-980. doi:10.1091/mbc.6.8.967
31. Gechtman Z, Alonso JL, Raab G, Ingber DE, Klagsbrun M. The shedding of membrane-anchored heparin-binding epidermal-like growth factor is regulated by the Raf/mitogen-activated protein kinase cascade and by cell adhesion and spreading. J Biol Chem. 1999;274(40):28828-28835. doi:10.1074/jbc.274.40.28828
32. Schaefer F and Rabkin R (2003) Insulin-like growth factor and the kidney. In: LeRoith D., Zumkeller W., Baxter R.C., editors. Insulin-like Growth Factors. Kluwer Academic/Plenum Publishers; New York: 2003. pp. 244–255.
33. Roelfsema V, Clark RG. The growth hormone and insulin-like growth factor axis: its manipulation for the benefit of growth disorders in renal failure. J Am Soc Nephrol. 2001;12(6):1297-1306. doi:10.1681/ASN.V1261297
34. Hirschberg R, Adler S. Insulin-like growth factor system and the kidney: physiology, pathophysiology, and therapeutic implications. Am J Kidney Dis. 1998;31(6):901-919. doi:10.1053/ajkd.1998.v31.pm9631833
35. Mathews LS, Hammer RE, Behringer RR, et al. Growth enhancement of transgenic mice expressing human insulin-like growth factor I. Endocrinology. 1988;123(6):2827-2833. doi:10.1210/endo-123-6-2827
36. Quaife CJ, Mathews LS, Pinkert CA, Hammer RE, Brinster RL, Palmiter RD. Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice. Endocrinology. 1989;124(1):40-48. doi:10.1210/endo-124-1-40
37. Doi T, Striker LJ, Gibson CC, Agodoa LY, Brinster RL, Striker GE. Glomerular lesions in mice transgenic for growth hormone and insulinlike growth factor-I. I. Relationship between increased glomerular size and mesangial sclerosis. Am J Pathol. 1990;137(3):541-552.
38. Franklin SC, Moulton M, Sicard GA, Hammerman MR, Miller SB. Insulin-like growth factor I preserves renal function postoperatively. Am J Physiol. 1997;272(2 Pt 2):F257-F259. doi:10.1152/ajprenal.1997.272.2.F257
39. Vijayan A, Franklin SC, Behrend T, Hammerman MR, Miller SB. Insulin-like growth factor I improves renal function in patients with end-stage chronic renal failure. Am J Physiol. 1999;276(4):R929-R934. doi:10.1152/ajpregu.1999.276.4.R929
40. Hammerman MR, Miller SB. Effects of growth hormone and insulin-like growth factor I on renal growth and function. J Pediatr. 1997;131(1 Pt 2):S17-S19. doi:10.1016/s0022-3476(97)70004-0
41. O'Shea MH, Miller SB, Hammerman MR. Effects of IGF-I on renal function in patients with chronic renal failure. Am J Physiol. 1993;264(5 Pt 2):F917-F922. doi:10.1152/ajprenal.1993.264.5.F917