Effects of high glucose on integrin activity and fibronectin matrix assembly by mesangial cells.

TitleEffects of high glucose on integrin activity and fibronectin matrix assembly by mesangial cells.
Publication TypeJournal Article
Year of Publication2014
AuthorsMiller, CG, Pozzi, A, Zent, R, Schwarzbauer, JE
JournalMol Biol Cell
Volume25
Issue16
Pagination2342-50
Date Published2014 Aug 15
ISSN1939-4586
KeywordsCells, Cultured, Collagen Type IV, Diabetic Nephropathies, Extracellular Matrix, Extracellular Matrix Proteins, Fibronectins, Glucose, Humans, Integrins, Mesangial Cells, Signal Transduction
Abstract

<p>The filtration unit of the kidney is the glomerulus, a capillary network supported by mesangial cells and extracellular matrix (ECM). Glomerular function is compromised in diabetic nephropathy (DN) by uncontrolled buildup of ECM, especially type IV collagen, which progressively occludes the capillaries. Increased levels of the ECM protein fibronectin (FN) are also present; however, its role in DN is unknown. Mesangial cells cultured under high glucose conditions provide a model system for studying the effect of elevated glucose on deposition of FN and collagen IV. Imaging of mesangial cell cultures and analysis of detergent-insoluble matrix show that, under high glucose conditions, mesangial cells assembled significantly more FN matrix, independent of FN protein levels. High glucose conditions induced protein kinase C-dependent β1 integrin activation, and FN assembly in normal glucose was increased by stimulation of integrin activity with Mn(2+). Collagen IV incorporation into the matrix was also increased under high glucose conditions and colocalized with FN fibrils. An inhibitor of FN matrix assembly prevented collagen IV deposition, demonstrating dependence of collagen IV on FN matrix. We conclude that high glucose induces FN assembly, which contributes to collagen IV accumulation. Enhanced assembly of FN might facilitate dysregulated ECM accumulation in DN.</p>

DOI10.1091/mbc.E14-03-0800
Alternate JournalMol. Biol. Cell
PubMed ID24943838
PubMed Central IDPMC4142608
Grant ListDK075594 / DK / NIDDK NIH HHS / United States
F30 DK095515 / DK / NIDDK NIH HHS / United States
F30-DK095515 / DK / NIDDK NIH HHS / United States
R01 CA160611 / CA / NCI NIH HHS / United States
R01 DK069921 / DK / NIDDK NIH HHS / United States
R01 DK075594 / DK / NIDDK NIH HHS / United States
R01 DK095761 / DK / NIDDK NIH HHS / United States
R01-CA160611 / CA / NCI NIH HHS / United States
R01-CA162433 / CA / NCI NIH HHS / United States
R01-DK083187 / DK / NIDDK NIH HHS / United States
R01-DK095761 / DK / NIDDK NIH HHS / United States
R01-DK383069221 / DK / NIDDK NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States