Vascular endothelial growth factor induces protein synthesis in renal epithelial cells: A potential role in diabetic nephropathy11See Editorial by Ziyadeh and Wolf, p. 758.

Aims/hypothesis An increasing amount of evidence indicates that mannose-binding lectin (MBL) plays a role in the development of diabetic nephropathy. The main objective of the study was to analyse whether MBL influences the effects of diabetes on the kidneys. Materials and methods In one group of wild-type mice and in one group of MBL double knockout mice we induced diabetes by the use of streptozotocin as a model of type 1 diabetes. Two groups of non-diabetic mice, wild-type and MBL knockout, were also included. By two-way ANOVA we evaluated if MBL modulated the effects of diabetes by testing the interaction between diabetes and MBL. Results MBL interacted with the effects of diabetes on three outcome measures: kidney weight (p<0.001), urinary albumin excretion (p=0.001) and the expression of collagen IVα1 (Col4a1) mRNA (p=0.002). This means that the effects that diabetes normally has on these parameters were significantly modified by MBL. MBL showed a tendency to interact with the effects of diabetes on glomerular basement membrane thickness and total mesangial volume (p=0.065 and p=0.063, respectively). Glomerular volume and total mesangial volume were significantly smaller in animals lacking MBL than in wild-type animals (p=0.006 and p=0.047, respectively). Conclusions/interpretation These findings, for the first time, show that the degree of kidney alteration as a consequence of diabetes is modified by MBL. These findings support a pivotal role of MBL in the development of diabetic kidney disease.

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“…in the STZ-diabetic rat [26][27][28][29][30]. In these studies the most pronounced upregulation was observed in the early stages of the disease.…”

Section: Discussionmentioning

confidence: 69%

Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice

et al. 2007

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“…In the present study, lean littermate control and diabetic mice were studied in the early phase, after 2 weeks of onset of hyperglycemia. The db/db mice develop renal hypertrophy at 2 weeks following onset of diabetes (18,19). Mice were sacrificed at the end of the experimental period, and renal cortex was dissected out and processed for further analysis.…”

Section: Methodsmentioning

confidence: 99%

“…8C). Reduction in expression of cystathionine ␤-synthase and cystathionine ␥-lyase occurred at a time when renal hypertrophy and onset of matrix laminin and type IV collagen accumulation are evident in these models of diabetes (17)(18)(19)41). These data suggest that conditions for decreased synthesis of hydrogen sulfide exist in the kidney in both type 1 and type 2 diabetes that would facilitate increased protein synthesis required for renal hypertrophy and matrix protein accumulation.…”

Section: Hydrogen Sulfide Decreases High Glucose-induced Proteinmentioning

confidence: 99%

Hydrogen Sulfide Inhibits High Glucose-induced Matrix Protein Synthesis by Activating AMP-activated Protein Kinase in Renal Epithelial Cells

Lee

Mariappan

Féliers

et al. 2012

Journal of Biological Chemistry

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113

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“…MCT cells express in vivo properties of proximal tubular epithelial cells (26). Confluent cells were growth-arrested for 18 h in serum-free Dulbecco's modified Eagle's medium before experiment (23).…”

Section: Methodsmentioning

confidence: 99%

Glycogen Synthase Kinase 3β Is a Novel Regulator of High Glucose- and High Insulin-induced Extracellular Matrix Protein Synthesis in Renal Proximal Tubular Epithelial Cells

Mariappan

Shetty

Sataranatarajan

et al. 2008

Journal of Biological Chemistry

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High glucose (30 mM) and high insulin (1 nM), pathogenic factors of type 2 diabetes, increased mRNA expression and synthesis of laminin ␤1 and fibronectin after 24 h of incubation in kidney proximal tubular epithelial (MCT) cells. We tested the hypothesis that inactivation of glycogen synthase kinase 3␤ (GSK3␤) by high glucose and high insulin induces increase in synthesis of laminin ␤1 via activation of eIF2B⑀. Both high glucose and high insulin induced Ser-9 phosphorylation and inactivation of GSK3␤ at 2 h that lasted for up to 48 h. This was associated with dephosphorylation of eIF2B⑀ and eEF2, and increase in phosphorylation of 4E-BP1 and eIF4E. Expression of the kinase-dead mutant of GSK3␤ or constitutively active kinase led to increased and diminished laminin ␤1 synthesis, respectively. Incubation with selective kinase inhibitors showed that high glucose-and high insulin-induced laminin ␤1 synthesis and phosphorylation of GSK3␤ were dependent on PI 3-kinase, Erk, and mTOR. High glucose and high insulin augmented activation of Akt, Erk, and p70S6 kinase. Dominant negative Akt, but not dominant negative p70S6 kinase, inhibited GSK3␤ phosphorylation induced by high glucose and high insulin, suggesting Akt but not p70S6 kinase was upstream of GSK3␤. Status of GSK3␤ was examined in vivo in renal cortex of db/db mice with type 2 diabetes at 2 weeks and 2 months of diabetes. Diabetic mice showed increased phosphorylation of renal cortical GSK3␤ and decreased phosphorylation of eIF2B⑀, which correlated with renal hypertrophy at 2 weeks, and increased laminin ␤1 and fibronectin protein content at 2 months. GSK3␤ and eIF2B⑀ play a role in augmented protein synthesis associated with high glucose-and high insulin-stimulated hypertrophy and matrix accumulation in renal disease in type 2 diabetes.Glycogen synthase kinase 3␤ (GSK3␤) 3 was originally identified as an enzyme required for the regulation of glycogen metabolism (1). However, it has been found to be involved in a variety of cellular responses including cytoskeletal regulation (2), cell cycle progression (3, 4), apoptosis (5, 6), and cell adhesion (7). GSK3␤ regulation of protein synthesis has not been completely understood. GSK3␤ acts as a switch that regulates both transcription and mRNA translation by controlling the activity of transcription factors and eukaryotic translation initiation factor 2B⑀ (eIF2B⑀), respectively. In the resting cell, GSK3␤ is unphosphorylated and active, inhibiting the activity of its substrates, e.g. eIF2B⑀ and glycogen synthase. Upon stimulation, GSK3␤ is phosphorylated on Ser-9 and inactivated, leading to release of inhibition on activity of its substrates. Several kinases are implicated in Ser-9 phosphorylation of GSK3␤ including p70S6 kinase (8), p90RSK (9), PKC, PKA (10 -12), and Akt (13,14).Augmented protein synthesis contributes to two cardinal manifestations of diabetic kidney disease, i.e. renal hypertrophy and accumulation of extracellular matrix proteins (15). However, the role of GSK3␤ in these events has not been inves...

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Vascular endothelial growth factor induces protein synthesis in renal epithelial cells: A potential role in diabetic nephropathy11See Editorial by Ziyadeh and Wolf, p. 758.

Cited by 69 publications

References 50 publications

Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice

Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice

Hydrogen Sulfide Inhibits High Glucose-induced Matrix Protein Synthesis by Activating AMP-activated Protein Kinase in Renal Epithelial Cells

Glycogen Synthase Kinase 3β Is a Novel Regulator of High Glucose- and High Insulin-induced Extracellular Matrix Protein Synthesis in Renal Proximal Tubular Epithelial Cells

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