Glucose Transporter Roles in the Development of Glomerulosclerosis

Main Article Content

Charles W. Heilig Alaa Awad Irtiza Hasan Ali Rawabdeh Yongxin Gao Vishal Jaikaransingh

Abstract

Extensive research has been done over the last several decades in pursuit of mechanisms leading to the glomerular disease and glomerulosclerosis in diabetic nephropathy. Much of the research investigated downstream pathways and terminal pathways to extracellular matrix production in the mesangial cells, after exposure to diabetes mellitus or high extracellular glucose concentrations. More recent research identified glucose transporter proteins expressed in normal and diabetic glomeruli, with the potential to regulate glucose uptake and metabolism in the glomerular mesangial cells. The mesangial cells are directly involved in excess matrix production in both diabetic and nondiabetic glomerulosclerosis. The common finding of excess glomerular glucose transporter expression in the development of both diabetic and nondiabetic glomerulosclerosis, provides a clue to how these glomerular lesions develop. Here, we review the potential roles of glucose transporter proteins, particularly facilitative glucose transporters (GLUTs), in enhancing mesangial cell glucose uptake, metabolism, and signaling to extracellular matrix expression which scars glomeruli. Both diabetes mellitus and glomerular hypertension without diabetes, have been shown to stimulate glomerular GLUT1 expression allowing for increased cellular glucose uptake. The stretch – inducible Mechano-Growth Factor recently identified in mesangial cells has the potential to translate glomerular hypertension with mesangial stretch in both diabetic and nondiabetic glomerular disease, into excess mesangial GLUT1 expression, glucose uptake and matrix production. Future research on this topic will likely be valuable. Positive feedback mechanisms are highlighted which can enhance mesangial GLUT1 expression to perpetuate glucose-induced matrix production and glomerular scarring in vivo.

Keywords: Glucose Transporter, GLUT, diabetic glomerulosclerosis, nondiabetic glomerulosclerosis, mesangial cell

Article Details

How to Cite
HEILIG, Charles W. et al. Glucose Transporter Roles in the Development of Glomerulosclerosis. Medical Research Archives, [S.l.], v. 12, n. 3, mar. 2024. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/5229>. Date accessed: 13 apr. 2024. doi: https://doi.org/10.18103/mra.v12i3.5229.
Section
Review Articles

References

1. Diabetes C, Complications Trial Research G, Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993, 329:977-86.

2. Group U: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998, 352:837-53.

3. Goldfarb S, Ziyadeh FN: TGF-beta: a crucial component of the pathogenesis of diabetic nephropathy. Trans Am Clin Climatol Assoc 2001, 112:27-32; discussion 3.

4. Chen S, Hong SW, Iglesias-de la Cruz MC, Isono M, Casaretto A, Ziyadeh FN: The key role of the transforming growth factor-beta system in the pathogenesis of diabetic nephropathy. Ren Fail 2001, 23:471-81.

5. Daroux M, Prevost G, Maillard-Lefebvre H, Gaxatte C, D'Agati VD, Schmidt AM, Boulanger E: Advanced glycation end-products: implications for diabetic and non-diabetic nephropathies. Diabetes Metab 2010, 36:1-10.

6. Henry DN, Busik JV, Brosius FC, 3rd, Heilig CW: Glucose transporters control gene expression of aldose reductase, PKCalpha, and GLUT1 in mesangial cells in vitro. Am J Physiol 1999, 277:F97-104.

7. Wang Y, Heilig K, Saunders T, Minto A, Deb DK, Chang A, Brosius F, Monteiro C, Heilig CW: Transgenic overexpression of GLUT1 in mouse glomeruli produces renal disease resembling diabetic glomerulosclerosis. Am J Physiol Renal Physiol 2010, 299:F99-F111.

8. Heilig CW, Liu Y, England RL, Freytag SO, Gilbert JD, Heilig KO, Zhu M, Concepcion LA, Brosius FC, 3rd: D-glucose stimulates mesangial cell GLUT1 expression and basal and IGF-I-sensitive glucose uptake in rat mesangial cells: implications for diabetic nephropathy. Diabetes 1997, 46:1030-9.

9. Pugliese G, Pricci F, Barsotti P, Iacobini C, Ricci C, Oddi G, Romeo G, Leto G, Marano G, Sorcini M, Sabbatini M, Fuiano G, Di Mario U, Pugliese F: Development of diabetic nephropathy in the Milan normotensive strain, but not in the Milan hypertensive strain: possible permissive role of hemodynamics. Kidney Int 2005, 67:1440-52.

10. Ricci C, Iacobini C, Oddi G, Amadio L, Menini S, Rastaldi MP, Frasheri A, Pricci F, Pugliese F, Pugliese G: Role of TGF-beta/ GLUT1 axis in susceptibility vs resistance to diabetic glomerulopathy in the Milan rat model. Nephrol Dial Transplant 2006, 21:1514-24.

11. Wang Y, Heilig KO, Minto AW, Chen S, Xiang M, Dean DA, Geiger RC, Chang A, Pravtcheva DD, Schlimme M, Deb DK, Wang Y, Heilig CW: Nephron-deficient Fvb mice develop rapidly progressive renal failure and heavy albuminuria involving excess glomerular GLUT1 and VEGF. Lab Invest 2010, 90:83-97.

12. Liu Z, Chen Z, Li Y: [Phenotypic and functional alterations of mesangial cells in patients with diabetic nephropathy]. Zhonghua Yi Xue Za Zhi 2001, 81:1369-73.

13. Mueckler M, Thorens B: The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med 2013, 34:121-38.

14. Heilig CW, Concepcion LA, Riser BL, Freytag SO, Zhu M, Cortes P: Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype. J Clin Invest 1995, 96:1802-14.

15. Pfafflin A, Brodbeck K, Heilig CW, Haring HU, Schleicher ED, Weigert C: Increased glucose uptake and metabolism in mesangial cells overexpressing glucose transporter 1 increases interleukin-6 and vascular endothelial growth factor production: role of AP-1 and HIF-1alpha. Cell Physiol Biochem 2006, 18:199-210.

16. Thorens B, Lodish HF, Brown D: Differential localization of two glucose transporter isoforms in rat kidney. Am J Physiol 1990, 259:C286-94.

17. Heilig C, Zaloga C, Lee M, Zhao X, Riser B, Brosius F, Cortes P: Immunogold localization of high-affinity glucose transporter isoforms in normal rat kidney. Lab Invest 1995, 73:674-84.

18. Brosius FC, 3rd, Briggs JP, Marcus RG, Barac-Nieto M, Charron MJ: Insulin-responsive glucose transporter expression in renal microvessels and glomeruli. Kidney Int 1992, 42:1086-92.

19. Marcus RG, England R, Nguyen K, Charron MJ, Briggs JP, Brosius FC, 3rd: Altered renal expression of the insulin-responsive glucose transporter GLUT4 in experimental diabetes mellitus. Am J Physiol 1994, 267:F816-24.

20. Asada T, Ogawa T, Iwai M, Shimomura K, Kobayashi M: Recombinant insulin-like growth factor I normalizes expression of renal glucose transporters in diabetic rats. Am J Physiol 1997, 273:F27-37.

21. Schiffer M, Susztak K, Ranalletta M, Raff AC, Bottinger EP, Charron MJ: Localization of the GLUT8 glucose transporter in murine kidney and regulation in vivo in nondiabetic and diabetic conditions. Am J Physiol Renal Physiol 2005, 289:F186-93.

22. Wakisaka M, He Q, Spiro MJ, Spiro RG: Glucose entry into rat mesangial cells is mediated by both Na(+)-coupled and facilitative transporters. Diabetologia 1995, 38:291-7.

23. Heilig CW, Brosius FC, 3rd, Henry DN: Glucose transporters of the glomerulus and the implications for diabetic nephropathy. Kidney Int Suppl 1997, 60:S91-9.

24. Heilig CW, Kreisberg JI, Freytag S, Murakami T, Ebina Y, Guo L, Heilig K, Loberg R, Qu X, Jin Y, Henry D, Brosius FC, 3rd: Antisense GLUT-1 protects mesangial cells from glucose induction of GLUT-1 and fibronectin expression. Am J Physiol Renal Physiol 2001, 280:F657-66.

25. Gao Y, James LR, Baher, AA, Shin, N, Bueno, EP, Heilig, CW. : High Glucose Induction of the GLUT1 Glucose Transporter and Mechano-Growth Factor (MGF) in Human Mesangial Cells (HMC) Portends Their Roles in Human Diabetic Nephropathy J Am Soc Nephrol 2017, 28:1023A.

26. Gnudi L, Viberti G, Raij L, Rodriguez V, Burt D, Cortes P, Hartley B, Thomas S, Maestrini S, Gruden G: GLUT-1 overexpression: Link between hemodynamic and metabolic factors in glomerular injury? Hypertension 2003, 42:19-24.

27. Gao, Y, Lee, H, Ramoutar,VR, Suliman, ST, Ilic, LM, Heilig, CW. Persistent Mechano-Growth Factor (MGF) Upregulation in Glomeruli of Diabetic or MGF-Transgenic Mice Induces Mesangial Cell (MC) Glucose Transport, PKC Activation, and Extracellular Matrix Production. J Am Soc Nephrol 2019, 30:908A.

28. Gao, Y, James, LR, Heilig, CW. Medicine, Univ of Florida College of Medicine-Jacksonville, Jacksonville, FL. : Mechano-Growth Factor Regulates mTOR and Other Growth Factor Expression in Mouse Mesangial Cells, Enhancing Cell Proliferation and Extracellular Matrix Production: Implications for Diabetic Glomerulosclerosis J Am Soc Nephrol 2015, 26:718A.

29. Heilig, CW. : Unpublished data.

30. Fernandes R, Carvalho AL, Kumagai A, Seica R, Hosoya K, Terasaki T, Murta J, Pereira P, Faro C: Downregulation of retinal GLUT1 in diabetes by ubiquitinylation. Mol Vis 2004, 10:618-28.

31. Ciaraldi TP, Mudaliar S, Barzin A, Macievic JA, Edelman SV, Park KS, Henry RR: Skeletal muscle GLUT1 transporter protein expression and basal leg glucose uptake are reduced in type 2 diabetes. J Clin Endocrinol Metab 2005, 90:352-8.

32. Giaccari A, Sorice G, Muscogiuri G: Glucose toxicity: the leading actor in the pathogenesis and clinical history of type 2 diabetes - mechanisms and potentials for treatment. Nutr Metab Cardiovasc Dis 2009, 19:365-77.

33. Dumler F, Cortes P: Uracil ribonucleotide metabolism in rat and human glomerular epithelial and mesangial cells. Am J Physiol 1988, 255:C712-8.

34.Breyer MD, Bottinger E, Brosius FC, 3rd, Coffman TM, Harris RC, Heilig CW, Sharma K, Amdcc: Mouse models of diabetic nephropathy. J Am Soc Nephrol 2005, 16:27-45.

35. Weigert C, Brodbeck K, Brosius FC, 3rd, Huber M, Lehmann R, Friess U, Facchin S, Aulwurm S, Haring HU, Schleicher ED, Heilig CW: Evidence for a novel TGF-beta1-independent mechanism of fibronectin production in mesangial cells overexpressing glucose transporters. Diabetes 2003, 52:527-35.

36. Chen SH Brosius FC, 3rd, Heilig C.: Diabetes increases glomerular GLUT1, and antisense-GLUT1 protects against diabetic glomerulosclerosis J Am Soc Nephrol 2003, 14:14A.

37. D'Agord Schaan B, Lacchini S, Bertoluci MC, Irigoyen MC, Machado UF, Schmid H: Increased renal GLUT1 abundance and urinary TGF-beta 1 in streptozotocin-induced diabetic rats: implications for the development of nephropathy complicating diabetes. Horm Metab Res 2001, 33:664-9.

38. Gunning P, Leavitt J, Muscat G, Ng SY, Kedes L: A human beta-actin expression vector system directs high-level accumulation of antisense transcripts. Proc Natl Acad Sci U S A 1987, 84:4831-5.

39. Zhang H, Schin M, Saha J, Burke K, Holzman LB, Filipiak W, Saunders T, Xiang M, Heilig CW, Brosius FC, 3rd: Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice. Am J Physiol Renal Physiol 2010, 299:F91-8.

40. Mohammed-Ali Z. Dahl Salt Sensitive Rat: Science Direct, 2006.

41. Brandis A, Bianchi G, Reale E, Helmchen U, Kuhn K: Age-dependent glomerulosclerosis and proteinuria occurring in rats of the Milan normotensive strain and not in rats of the Milan hypertensive strain. Lab Invest 1986, 55:234-43.

42. Oppermann M, Castrop H, Mizel D, Heilig K, Heilig CW, Schnermann J,: Glomerular hypertension and hyperfiltration in young fvb.ROP Os/+ mice. Faseb J 2007, 21:A503.

43. Zheng F, Striker GE, Esposito C, Lupia E, Striker LJ: Strain differences rather than hyperglycemia determine the severity of glomerulosclerosis in mice. Kidney Int 1998, 54:1999-2007.

44. Esposito C, He CJ, Striker GE, Zalups RK, Striker LJ: Nature and severity of the glomerular response to nephron reduction is strain-dependent in mice. Am J Pathol 1999, 154:891-7.

45. He C, Esposito C, Phillips C, Zalups RK, Henderson DA, Striker GE, Striker LJ: Dissociation of glomerular hypertrophy, cell proliferation, and glomerulosclerosis in mouse strains heterozygous for a mutation (Os) which induces a 50% reduction in nephron number. J Clin Invest 1996, 97:1242-9.

46. Vera JC, Reyes AM, Velasquez FV, Rivas CI, Zhang RH, Strobel P, Slebe JC, Nunez-Alarcon J, Golde DW: Direct inhibition of the hexose transporter GLUT1 by tyrosine kinase inhibitors. Biochemistry 2001, 40:777-90.

47. Deb DK, Heilig CW, et al: Prevention of Diabetes−Induced Signaling Agent and Matrix Expression by Glomerular Antisense−GLUT1 In Vivo, and by Mesangial Cell (MC) Antisense−GLUT1 and Quercetin Treatment In Vitro. J am Soc Nephrol (abstr.) 2009.

48. Gao, Y, Heilig, CW. : FVB Os/+ Mesangial Cells Exhibit Enhanced mTOR and Growth Factor Expression, Modeling the FVB Os/+ Glomerulosclerosis Mouse J Am Soc Nephrol 2015, 26:722A.

49. Kriz W, Elger M, Lemley K, Sakai T: Structure of the glomerular mesangium: a biomechanical interpretation. Kidney Int Suppl 1990, 30:S2-9.

50. Heilig CW, Brosius FC, 3rd, Cunningham C: Role for GLUT1 in diabetic glomerulosclerosis. Expert Rev Mol Med 2006, 8:1-18.

51. Murakami T, Nishiyama T, Shirotani T, Shinohara Y, Kan M, Ishii K, Kanai F, Nakazuru S, Ebina Y: Identification of two enhancer elements in the gene encoding the type 1 glucose transporter from the mouse which are responsive to serum, growth factor, and oncogenes. J Biol Chem 1992, 267:9300-6.