Lysosomal enzymes, metalloproteinases and proteoglycans in Diabetes mellitus

• Grant number: 10/16022-5
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2010
• End date: November 30, 2012
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Yara Maria Corrêa da Silva Michelacci
• Grantee: Yara Maria Corrêa da Silva Michelacci
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Ivarne Luis dos Santos Tersariol ; Jair Adriano Kopke de Aguiar

Abstract

A hallmark in diabetes mellitus is microangiopathy, with capillary basement membrane thickening and loss of normal function in capillary bed. Although these changes occur in all tissues, many studies focus the kidney because the glomerulus contain abundant and concentrated capillar basement membrane, and also because diabetic nephropathy is one of the most serious and frequent consequences of diabetes mellitus.Albuminuria characterizes diabetic nephropathy, and both basement membrane thickening and mesangial matrix expansion occur. The concentrations of dermatan sulfate and chondroitin sulfate proteoglycans, but not heparan sulfate proteoglycans, is increased in diabetic kidney, especially in glomerulus. Surprisingly, the urinary excretion of glycosaminoglycans and other sulfated polysaccharides is very decreased, and this is a very early event in diabetic nephropathy. This apparent paradox - increase in the urinary excretion of albumin and decrease in the excretion of sulfated polysaccharides - suggests different pathways for the urinary excretion of these macromolecules, possibly involving cells. The traditional view is that the albuminuria is the result of damage to an essentially impermeable glomerular barrier. Recent evidences, however, indicate that although the glomerular filter offers a significant barrier to albumin, it is imperfect, and the barrier leaks albumin. The proximal tubule cells retrieve most of the filtered albumin, to return it back to the blood supply. A small amount is directed toward lysosomal degradation, and the peptide products are exocytosed in the tubular lumen and excreted. So, albuminuria would be a tubular, not a glomerular, disease.Under normal turnover conditions, the extracellular matrix macromolecules are substrates for neutral metalloproteinases and glycosidases, and the partial degradation products are directed toward lysosomes for complete digestion. In diabetes mellitus, the important changes in composition and architecture of extracellular matrix, as well as the modifications in the urinary excretion of macromolecules, suggest that changes in the expression and activities of lysosomal enzymes and matrix metalloproteinases and glycosidases could occur.The aim of the present study is to investigate this hypothesis. Possible changes in the expression (mRNA and protein) and activities of lysosomal enzymes (catepsins, glycosidases and sulfatases) and of metalloproteinases will be investigated in rat kidney and liver during the acute phase of diabetes mellitus (10 days and 30 days). The extracellular matrix proteoglycans will also be analyzed.This study will increase our knowledge about the metabolism and turnover of extracellular matrix in diabetes mellitus. Furthermore, it may lead to the suggestion of new targets for prevention and treatment of nephropathy in diabetic patients. (AU)

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DA CUNHA, ANDRE L.; AGUIAR, JAIR A. K.; CORREA DA SILVA, FLAVIO S.; MICHELACCI, YARA M.. Do chondroitin sulfates with different structures have different activities on chondrocytes and macrophages?. International Journal of Biological Macromolecules, v. 103, p. 1019-1031, OCT 2017. (10/16022-5, 13/07109-8)

G.B. PERES; M.A. JULIANO; J.A.K. AGUIAR; Y.M. MICHELACCI. Streptozotocin-induced diabetes mellitus affects lysosomal enzymes in rat liver. Brazilian Journal of Medical and Biological Research, v. 47, n. 6, p. 452-460, 2014-05-09. (09/11817-2, 10/16022-5, 13/07109-8)

PERES, GIOVANI B.; JULIANO, MARIA A.; SIMOES, MANUEL J.; MICHELACCI, YARA M.. Lysosomal enzymes are decreased in the kidney of diabetic rats. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v. 1832, n. 1, p. 85-95, JAN 2013. (10/16022-5, 09/11817-2)

DA CUNHA, ANDRE LUIZ; DE OLIVEIRA, LUIZ GUSTAVO; MAIA, LENIZE FERNANDES; CAPPA DE OLIVEIRA, LUIZ FERNANDO; MICHELACCI, YARA M.; DE AGUIAR, JAIR ADRIANO K.. Pharmaceutical grade chondroitin sulfate: Structural analysis and identification of contaminants in different commercial preparations. Carbohydrate Polymers, v. 134, p. 300-308, DEC 10 2015. (10/16022-5)

NEUENSCHWANDER, HENRIQUE M.; MOREIRA, JULIANA J.; VENDRUSCOLO, CYNTHIA P.; FULBER, JOICE; SEIDEL, SARAH R. T.; MICHELACCI, YARA M.; BACCARIN, RAQUEL Y. A.. Hyaluronic acid has chondroprotective and joint-preserving effects on LPS-induced synovitis in horses. Journal of Veterinary Science, v. 20, n. 6, NOV 2019. (10/16022-5, 14/13065-6, 13/07109-8)

MICHELACCI, YARA M.; BACCARIN, RAQUEL Y. A.; RODRIGUES, NUBIA N. P.. Chondrocyte Homeostasis and Differentiation: Transcriptional Control and Signaling in Healthy and Osteoarthritic Conditions. LIFE-BASEL, v. 13, n. 7, p. 20-pg., 2023-07-01. (13/07109-8, 10/16022-5, 15/03964-6)

PERES, GIOVANI B.; SCHOR, NESTOR; MICHELACCI, YARA M.. Impact of high glucose and AGEs on cultured kidney-derived cells. Effects on cell viability, lysosomal enzymes and effectors of cell signaling pathways. Biochimie, v. 135, p. 137-148, APR 2017. (10/16022-5, 15/03964-6, 13/07109-8)