Abstract
Previous studies revealed that exposure of mesangial cells to high glucose concentration induces the production of matrix proteins mediated by TGF-beta1. We tested if structural analogues of D-glucose may mimic the high glucose effect and found that D-glucosamine was strikingly more potent than D-glucose itself in enhancing the production of TGF-beta protein and subsequent production of the matrix components heparan sulfate proteoglycan and fibronectin in a time- and dose-dependent manner. D-Glucosamine also promoted conversion of latent TGF-beta to the active form. Therefore, we suggested that the hexosamine biosynthetic pathway (the key enzyme of which is glutamine:fructose-6-phosphate amidotransferase [GFAT]) contributes to the high glucose-induced TGF-beta1 production. Inhibition of GFAT by the substrate analogue azaserine or by inhibition of GFAT protein synthesis with antisense oligonucleotide prevented the high glucose-induced increase in cellular glucosamine metabolites and TGF-beta1 expression and bioactivity and subsequent effects on mesangial cell proliferation and matrix production. Overall, our study indicates that the flux of glucose metabolism through the GFAT catalyzed hexosamine biosynthetic pathway is involved in the glucose-induced mesangial production of TGF-beta leading to increased matrix production.
Full Text
The Full Text of this article is available as a PDF (267.9 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Abrass C. K., Peterson C. V., Raugi G. J. Phenotypic expression of collagen types in mesangial matrix of diabetic and nondiabetic rats. Diabetes. 1988 Dec;37(12):1695–1702. doi: 10.2337/diab.37.12.1695. [DOI] [PubMed] [Google Scholar]
- Ayo S. H., Radnik R., Garoni J. A., Troyer D. A., Kreisberg J. I. High glucose increases diacylglycerol mass and activates protein kinase C in mesangial cell cultures. Am J Physiol. 1991 Oct;261(4 Pt 2):F571–F577. doi: 10.1152/ajprenal.1991.261.4.F571. [DOI] [PubMed] [Google Scholar]
- Border W. A., Okuda S., Languino L. R., Ruoslahti E. Transforming growth factor-beta regulates production of proteoglycans by mesangial cells. Kidney Int. 1990 Feb;37(2):689–695. doi: 10.1038/ki.1990.35. [DOI] [PubMed] [Google Scholar]
- Buse M. G., Robinson K. A., Marshall B. A., Mueckler M. Differential effects of GLUT1 or GLUT4 overexpression on hexosamine biosynthesis by muscles of transgenic mice. J Biol Chem. 1996 Sep 20;271(38):23197–23202. doi: 10.1074/jbc.271.38.23197. [DOI] [PubMed] [Google Scholar]
- Ceol M., Nerlich A., Baggio B., Anglani F., Sauer U., Schleicher E., Gambaro G. Increased glomerular alpha 1 (IV) collagen expression and deposition in long-term diabetic rats is prevented by chronic glycosaminoglycan treatment. Lab Invest. 1996 Feb;74(2):484–495. [PubMed] [Google Scholar]
- Coimbra T., Wiggins R., Noh J. W., Merritt S., Phan S. H. Transforming growth factor-beta production in anti-glomerular basement membrane disease in the rabbit. Am J Pathol. 1991 Jan;138(1):223–234. [PMC free article] [PubMed] [Google Scholar]
- Crowley S. T., Brownlee M., Edelstein D., Satriano J. A., Mori T., Singhal P. C., Schlondorff D. O. Effects of nonenzymatic glycosylation of mesangial matrix on proliferation of mesangial cells. Diabetes. 1991 May;40(5):540–547. doi: 10.2337/diab.40.5.540. [DOI] [PubMed] [Google Scholar]
- Daniels M. C., Ciaraldi T. P., Nikoulina S., Henry R. R., McClain D. A. Glutamine:fructose-6-phosphate amidotransferase activity in cultured human skeletal muscle cells: relationship to glucose disposal rate in control and non-insulin-dependent diabetes mellitus subjects and regulation by glucose and insulin. J Clin Invest. 1996 Mar 1;97(5):1235–1241. doi: 10.1172/JCI118538. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Daniels M. C., Kansal P., Smith T. M., Paterson A. J., Kudlow J. E., McClain D. A. Glucose regulation of transforming growth factor-alpha expression is mediated by products of the hexosamine biosynthesis pathway. Mol Endocrinol. 1993 Aug;7(8):1041–1048. doi: 10.1210/mend.7.8.8232303. [DOI] [PubMed] [Google Scholar]
- Danne T., Spiro M. J., Spiro R. G. Effect of high glucose on type IV collagen production by cultured glomerular epithelial, endothelial, and mesangial cells. Diabetes. 1993 Jan;42(1):170–177. doi: 10.2337/diab.42.1.170. [DOI] [PubMed] [Google Scholar]
- Doi T., Vlassara H., Kirstein M., Yamada Y., Striker G. E., Striker L. J. Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2873–2877. doi: 10.1073/pnas.89.7.2873. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fukui M., Nakamura T., Ebihara I., Shirato I., Tomino Y., Koide H. ECM gene expression and its modulation by insulin in diabetic rats. Diabetes. 1992 Dec;41(12):1520–1527. doi: 10.2337/diab.41.12.1520. [DOI] [PubMed] [Google Scholar]
- Heilig C. W., Concepcion L. A., Riser B. L., Freytag S. O., 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 Oct;96(4):1802–1814. doi: 10.1172/JCI118226. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Isaka Y., Fujiwara Y., Ueda N., Kaneda Y., Kamada T., Imai E. Glomerulosclerosis induced by in vivo transfection of transforming growth factor-beta or platelet-derived growth factor gene into the rat kidney. J Clin Invest. 1993 Dec;92(6):2597–2601. doi: 10.1172/JCI116874. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Iwano M., Kubo A., Nishino T., Sato H., Nishioka H., Akai Y., Kurioka H., Fujii Y., Kanauchi M., Shiiki H. Quantification of glomerular TGF-beta 1 mRNA in patients with diabetes mellitus. Kidney Int. 1996 Apr;49(4):1120–1126. doi: 10.1038/ki.1996.162. [DOI] [PubMed] [Google Scholar]
- Kagami S., Border W. A., Miller D. E., Noble N. A. Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest. 1994 Jun;93(6):2431–2437. doi: 10.1172/JCI117251. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kim Y., Butkowski R., Burke B., Kleppel M. M., Crosson J., Katz A., Michael A. F. Differential expression of basement membrane collagen in membranous nephropathy. Am J Pathol. 1991 Dec;139(6):1381–1388. [PMC free article] [PubMed] [Google Scholar]
- Kolm V., Sauer U., Olgemöller B., Schleicher E. D. High glucose-induced TGF-beta 1 regulates mesangial production of heparan sulfate proteoglycan. Am J Physiol. 1996 May;270(5 Pt 2):F812–F821. doi: 10.1152/ajprenal.1996.270.5.F812. [DOI] [PubMed] [Google Scholar]
- Kreisberg J. I., Ayo S. H. The glomerular mesangium in diabetes mellitus. Kidney Int. 1993 Jan;43(1):109–113. doi: 10.1038/ki.1993.18. [DOI] [PubMed] [Google Scholar]
- Larkins R. G., Dunlop M. E. The link between hyperglycaemia and diabetic nephropathy. Diabetologia. 1992 Jun;35(6):499–504. doi: 10.1007/BF00400475. [DOI] [PubMed] [Google Scholar]
- Ledbetter S., Copeland E. J., Noonan D., Vogeli G., Hassell J. R. Altered steady-state mRNA levels of basement membrane proteins in diabetic mouse kidneys and thromboxane synthase inhibition. Diabetes. 1990 Feb;39(2):196–203. doi: 10.2337/diab.39.2.196. [DOI] [PubMed] [Google Scholar]
- Marshall S., Bacote V., Traxinger R. R. Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. J Biol Chem. 1991 Mar 15;266(8):4706–4712. [PubMed] [Google Scholar]
- Marshall S., Garvey W. T., Traxinger R. R. New insights into the metabolic regulation of insulin action and insulin resistance: role of glucose and amino acids. FASEB J. 1991 Dec;5(15):3031–3036. doi: 10.1096/fasebj.5.15.1743436. [DOI] [PubMed] [Google Scholar]
- McClain D. A., Crook E. D. Hexosamines and insulin resistance. Diabetes. 1996 Aug;45(8):1003–1009. doi: 10.2337/diab.45.8.1003. [DOI] [PubMed] [Google Scholar]
- McClain D. A., Paterson A. J., Roos M. D., Wei X., Kudlow J. E. Glucose and glucosamine regulate growth factor gene expression in vascular smooth muscle cells. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8150–8154. doi: 10.1073/pnas.89.17.8150. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McKnight G. L., Mudri S. L., Mathewes S. L., Traxinger R. R., Marshall S., Sheppard P. O., O'Hara P. J. Molecular cloning, cDNA sequence, and bacterial expression of human glutamine:fructose-6-phosphate amidotransferase. J Biol Chem. 1992 Dec 15;267(35):25208–25212. [PubMed] [Google Scholar]
- Mohan P. S., Carter W. G., Spiro R. G. Occurrence of type VI collagen in extracellular matrix of renal glomeruli and its increase in diabetes. Diabetes. 1990 Jan;39(1):31–37. doi: 10.2337/diacare.39.1.31. [DOI] [PubMed] [Google Scholar]
- Nahman N. S., Jr, Leonhart K. L., Cosio F. G., Hebert C. L. Effects of high glucose on cellular proliferation and fibronectin production by cultured human mesangial cells. Kidney Int. 1992 Feb;41(2):396–402. doi: 10.1038/ki.1992.55. [DOI] [PubMed] [Google Scholar]
- Nakamura T., Fukui M., Ebihara I., Osada S., Nagaoka I., Tomino Y., Koide H. mRNA expression of growth factors in glomeruli from diabetic rats. Diabetes. 1993 Mar;42(3):450–456. doi: 10.2337/diab.42.3.450. [DOI] [PubMed] [Google Scholar]
- Nerlich A. G., Schleicher E. D., Wiest I., Specks U., Timpl R. Immunohistochemical localization of collagen VI in diabetic glomeruli. Kidney Int. 1994 Jun;45(6):1648–1656. doi: 10.1038/ki.1994.216. [DOI] [PubMed] [Google Scholar]
- Nerlich A., Schleicher E. Immunohistochemical localization of extracellular matrix components in human diabetic glomerular lesions. Am J Pathol. 1991 Oct;139(4):889–899. [PMC free article] [PubMed] [Google Scholar]
- Olgemöller B., Schleicher E. D., Schwaabe S., Guretzki H. J., Gerbitz K. D. High concentrations of low density lipoprotein decrease basement membrane-associated heparan sulfate proteoglycan in cultured endothelial cells. FEBS Lett. 1990 May 7;264(1):37–39. doi: 10.1016/0014-5793(90)80758-b. [DOI] [PubMed] [Google Scholar]
- Olgemöller B., Schleicher E., Nerlich A., Wagner E. M., Gerbitz K. D. Isolation, characterization and immunological determination of basement membrane-associated heparan sulfate proteoglycan. Biol Chem Hoppe Seyler. 1989 Dec;370(12):1321–1329. doi: 10.1515/bchm3.1989.370.2.1321. [DOI] [PubMed] [Google Scholar]
- Osterby R., Gall M. A., Schmitz A., Nielsen F. S., Nyberg G., Parving H. H. Glomerular structure and function in proteinuric type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993 Oct;36(10):1064–1070. doi: 10.1007/BF02374500. [DOI] [PubMed] [Google Scholar]
- Osterby R. Glomerular structural changes in type 1 (insulin-dependent) diabetes mellitus: causes, consequences, and prevention. Diabetologia. 1992 Sep;35(9):803–812. doi: 10.1007/BF00399925. [DOI] [PubMed] [Google Scholar]
- Pugliese G., Pricci F., Pugliese F., Mene P., Lenti L., Andreani D., Galli G., Casini A., Bianchi S., Rotella C. M. Mechanisms of glucose-enhanced extracellular matrix accumulation in rat glomerular mesangial cells. Diabetes. 1994 Mar;43(3):478–490. doi: 10.2337/diab.43.3.478. [DOI] [PubMed] [Google Scholar]
- Rocco M. V., Chen Y., Goldfarb S., Ziyadeh F. N. Elevated glucose stimulates TGF-beta gene expression and bioactivity in proximal tubule. Kidney Int. 1992 Jan;41(1):107–114. doi: 10.1038/ki.1992.14. [DOI] [PubMed] [Google Scholar]
- Rossetti L., Hawkins M., Chen W., Gindi J., Barzilai N. In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats. J Clin Invest. 1995 Jul;96(1):132–140. doi: 10.1172/JCI118013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schleicher E., Nerlich A. The role of hyperglycemia in the development of diabetic complications. Horm Metab Res. 1996 Aug;28(8):367–373. doi: 10.1055/s-2007-979817. [DOI] [PubMed] [Google Scholar]
- Sharma K., Jin Y., Guo J., Ziyadeh F. N. Neutralization of TGF-beta by anti-TGF-beta antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes. 1996 Apr;45(4):522–530. doi: 10.2337/diab.45.4.522. [DOI] [PubMed] [Google Scholar]
- Sharma K., Ziyadeh F. N. Hyperglycemia and diabetic kidney disease. The case for transforming growth factor-beta as a key mediator. Diabetes. 1995 Oct;44(10):1139–1146. doi: 10.2337/diab.44.10.1139. [DOI] [PubMed] [Google Scholar]
- Silbiger S., Schlondorff D., Crowley S., Rosenberg L., Choi H., Hatcher V., Gordon P. The effect of glucose on proteoglycans produced by cultured mesangial cells. Diabetes. 1993 Dec;42(12):1815–1822. doi: 10.2337/diab.42.12.1815. [DOI] [PubMed] [Google Scholar]
- Steffes M. W., Bilous R. W., Sutherland D. E., Mauer S. M. Cell and matrix components of the glomerular mesangium in type I diabetes. Diabetes. 1992 Jun;41(6):679–684. doi: 10.2337/diab.41.6.679. [DOI] [PubMed] [Google Scholar]
- Studer R. K., Craven P. A., DeRubertis F. R. Role for protein kinase C in the mediation of increased fibronectin accumulation by mesangial cells grown in high-glucose medium. Diabetes. 1993 Jan;42(1):118–126. doi: 10.2337/diab.42.1.118. [DOI] [PubMed] [Google Scholar]
- Wakisaka M., Spiro M. J., Spiro R. G. Synthesis of type VI collagen by cultured glomerular cells and comparison of its regulation by glucose and other factors with that of type IV collagen. Diabetes. 1994 Jan;43(1):95–103. doi: 10.2337/diab.43.1.95. [DOI] [PubMed] [Google Scholar]
- Wolf G., Sharma K., Chen Y., Ericksen M., Ziyadeh F. N. High glucose-induced proliferation in mesangial cells is reversed by autocrine TGF-beta. Kidney Int. 1992 Sep;42(3):647–656. doi: 10.1038/ki.1992.330. [DOI] [PubMed] [Google Scholar]
- Yamamoto T., Nakamura T., Noble N. A., Ruoslahti E., Border W. A. Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1814–1818. doi: 10.1073/pnas.90.5.1814. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ziyadeh F. N., Sharma K., Ericksen M., Wolf G. Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor-beta. J Clin Invest. 1994 Feb;93(2):536–542. doi: 10.1172/JCI117004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ziyadeh F. N. The extracellular matrix in diabetic nephropathy. Am J Kidney Dis. 1993 Nov;22(5):736–744. doi: 10.1016/s0272-6386(12)80440-9. [DOI] [PubMed] [Google Scholar]