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High Glucose, High Insulin, and Their Combination Rapidly Induce Laminin-ß1 Synthesis by Regulation of mRNA Translation in Renal Epithelial Cells

¹ O’Brien Kidney Research Center, Department of Medicine, University of Texas Health Science Center, South Texas Veterans Health Care System, GRECC San Antonio, Texas
² Division of Infectious Diseases, Department of Medicine, University of Texas Health Science Center, South Texas Veterans Health Care System, GRECC San Antonio, Texas
³ South Texas Veterans Health Care System, GRECC San Antonio, Texas

Address correspondence and reprint requests to Balakuntalam S. Kasinath, MD, Department of Medicine, MC7882, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229. E-mail: kasinath{at}uthscsa.edu

Abbreviations: AMPK, AMP-activated protein kinase; DMEM, Dulbecco’s modified Eagle’s medium; ECM, extracellular matrix; eIF4E, eukaryotic initiation factor 4E; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MAP, mitogen-activated protein; MCT, mouse cortical tubule; mTOR, mammalian target of rapamycin; PI 3-kinase, phosphatidylinositol 3-kinase; PI3P, phosphatidylinositol 3 phosphate; TCA, trichloroacetic acid; VEGF, vascular endothelial growth factor

Laminin is a glycoprotein that contributes to renal extracellular matrix expansion in diabetes. We investigated regulation of laminin-ß1 synthesis in murine renal proximal tubular epithelial cells by 30 mmol/l glucose (high glucose), 1 nmol/l insulin (high insulin), and their combination (high glucose+high insulin), simulating conditions observed during progression of type 2 diabetes. Compared with 5 mmol/l glucose and no insulin (control), high glucose alone, high insulin alone, or high glucose+high insulin together increased laminin-ß1 chain protein synthesis within 5 min, lasting for up to 60 min with no change in laminin-ß1 mRNA levels. Cycloheximide, but not actinomycin-D, abrogated increased laminin-ß1 synthesis. High glucose, high insulin, and high glucose+high insulin stimulated phosphorylation of 4E-BP1, a repressor binding protein for eukaryotic initiation factor 4E (eIF4E), that was dependent on activation of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin. High glucose, high insulin, and high glucose+high insulin also promoted release of eIF4E from 4E-BP1, phosphorylation of eIF4E, and increase in eIF4E association with eIF4G, critical events in the initiation phase of mRNA translation. High glucose, high insulin, and high glucose+high insulin increased Erk phosphorylation, which is an upstream regulator of eIF4E phosphorylation, and PD098059, which is a MEK inhibitor that blocks Erk activation, abolished laminin-ß1 synthesis. This is the first demonstration of rapid increment in laminin-ß1 synthesis by regulation of its mRNA translation by cells exposed to high glucose, high insulin, or high glucose+high insulin.

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