Influence of glucosamine on glomerular mesangial cell turnover: implications for hyperglycemia and hexosamine pathway flux

James, Leighton R.; Le, Catherine; Scholey, James W.

doi:10.1152/ajpendo.00232.2009

Cited by 10 publications

(9 citation statements)

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“…It has been observed that exposure to high levels of GlcN could cause apoptosis as well ( 27 , 28 ) . Previous studies have proved that protracted exposure to a high dose of GlcN leads to the apoptosis of mesangial cells in a manner that is similar to that observed in high-glucose conditions ( 29 ) . In the present study, we observed that mesangial cell apoptosis was induced by the treatment with 15 m m -GlcN.…”

Section: Discussionmentioning

confidence: 59%

Grape seed procyanidin B2 ameliorates mitochondrial dysfunction and inhibits apoptosis via the AMP-activated protein kinase–silent mating type information regulation 2 homologue 1–PPARγ co-activator-1α axis in rat mesangial cells under high-dose glucosamine

et al. 2014

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Grape seed procyanidin B2 (GSPB2), an antioxidative and anti-inflammatory polyphenol in grape seed, has been found to have protective effects on diabetic nephropathy. Based on its favourable biological activities, in the present study, we aimed to investigate whether GSPB2 could inhibit apoptosis in rat mesangial cells treated with glucosamine (GlcN) under high-dose conditions. The results showed that the administration of GSPB2 (10 mg/ml) significantly increased the viability of mesangial cells treated with GlcN at a dose of 15 mM. We found that GSPB2 inhibited apoptosis in mesangial cells using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphates (dUTP) nick-end labelling staining and flow cytometry technique (P,0·05 for both). GSPB2 treatment also suppressed oxidative stress by elevating the activity of glutathione peroxidase (P,0·05) and superoxide dismutase (P,0·01), as well as prevented cellular damage. GSPB2 enhanced the mRNA expression of nuclear respiratory factor 1, mitochondrial transcription factor A and mitochondrial DNA copy number in mesangial cells as determined by real-time PCR (P,0·05 for each). Finally, GSPB2 treatment activated the protein expression of PPARg co-activator-1a (PGC-1a), silent mating type information regulation 2 homologue 1 (SIRT1) and AMP-activated protein kinase (AMPK) in mesangial cells. These findings suggest that GSPB2 markedly ameliorates mitochondrial dysfunction and inhibits apoptosis in rat mesangial cells treated with high-dose GlcN. This protective effect could be, at least in part, due to the activation of the AMPK-SIRT1-PGC-1a axis.

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Section: Discussionmentioning

confidence: 59%

Grape seed procyanidin B2 ameliorates mitochondrial dysfunction and inhibits apoptosis via the AMP-activated protein kinase–silent mating type information regulation 2 homologue 1–PPARγ co-activator-1α axis in rat mesangial cells under high-dose glucosamine

et al. 2014

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“…Du et al (150) and Federici et al (165) reported that hexosamine pathway-induced modification of eNOS protein interferes with its activation by phosphorylation thereby resulting in a reduced ability of eNOS to produce NO. More recent studies have also implicated the pathway in mesangial proliferation mediated by rapamycin-sensitive mTOR complex 1 (mTORC1) as well as in mesangial apoptosis (272). Further studies are necessary to define the relevance of the hexosamine pathway in the diabetic kidney in vivo.…”

Section: General Mechanisms Of Glucose-induced Cell Injurymentioning

confidence: 99%

Pathophysiology of the Diabetic Kidney

Vallon

Komers

2011

Comprehensive Physiology

228

178

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Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the molecular mechanism involved and of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. Here we review the pathophysiological changes that occur in the kidney in response to hyperglycemia, including the cellular responses to high glucose and the responses in vascular, glomerular, podocyte, and tubular function. The molecular basis, characteristics, and consequences of the unique growth phenotypes observed in the diabetic kidney, including glomerular structures and tubular segments, are outlined. We delineate mechanisms of early diabetic glomerular hyperfiltration including primary vascular events as well as the primary role of tubular growth, hyperreabsorption, and tubuloglomerular communication as part of a “tubulocentric” concept of early diabetic kidney function. The latter also explains the “salt paradox” of the diabetic kidney, that is, a unique and inverse relationship between glomerular filtration rate and dietary salt intake. The mechanisms and consequences of the intrarenal activation of the renin-angiotensin system and of diabetes-induced tubular glycogen accumulation are discussed. Moreover, we aim to link the changes that occur early in the diabetic kidney including the growth phenotype, oxidative stress, hypoxia, and formation of advanced glycation end products to mechanisms involved in progressive kidney disease.

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“…The importance of the mTORC1 complex was demonstrated in diabetic renal pathology, and rapamycin is experimentally used as a therapeutic agent against the progression of diabetic nephropathy [23] , [40] , [41] . The AKT/mTOR pathway plays a role in HG-induced mesangial cell proliferation [42] , as well as mesangial and glomerular hypertrophy [43] . Moreover, inhibition of mTOR by rapamycin downregulates these effects [42] , [43] .…”

Section: Discussionmentioning

confidence: 99%

AS101 Prevents Diabetic Nephropathy Progression and Mesangial Cell Dysfunction: Regulation of the AKT Downstream Pathway

et al. 2014

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Diabetic nephropathy (DN) is characterized by proliferation of mesangial cells, mesangial expansion, hypertrophy and extracellular matrix accumulation. Previous data have cross-linked PKB (AKT) to TGFβ induced matrix modulation. The non-toxic compound AS101 has been previously shown to favorably affect renal pathology in various animal models and inhibits AKT activity in leukemic cells. Here, we studied the pharmacological properties of AS101 against the progression of rat DN and high glucose-induced mesangial dysfunction. In-vivo administration of AS101 to Streptozotocin injected rats didn’t decreased blood glucose levels but ameliorated kidney hypotrophy, proteinuria and albuminuria and downregulated cortical kidney phosphorylation of AKT, GSK3β and SMAD3. AS101 treatment of primary rat glomerular mesangial cells treated with high glucose significantly reduced their elevated proliferative ability, as assessed by XTT assay and cell cycle analysis. This reduction was associated with decreased levels of p-AKT, increased levels of PTEN and decreased p-GSK3β and p-FoxO3a expression. Pharmacological inhibition of PI3K, mTORC1 and SMAD3 decreased HG-induced collagen accumulation, while inhibition of GSK3β did not affect its elevated levels. AS101 also prevented HG-induced cell growth correlated to mTOR and (rp)S6 de-phosphorylation. Thus, pharmacological inhibition of the AKT downstream pathway by AS101 has clinical potential in alleviating the progression of diabetic nephropathy.

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Influence of glucosamine on glomerular mesangial cell turnover: implications for hyperglycemia and hexosamine pathway flux

Abstract: James LR, Le C, Scholey JW. Influence of glucosamine on glomerular mesangial cell turnover: implications for hyperglycemia and hexosamine pathway flux.

Cited by 10 publications

References 70 publications

Grape seed procyanidin B2 ameliorates mitochondrial dysfunction and inhibits apoptosis via the AMP-activated protein kinase–silent mating type information regulation 2 homologue 1–PPARγ co-activator-1α axis in rat mesangial cells under high-dose glucosamine

Grape seed procyanidin B2 ameliorates mitochondrial dysfunction and inhibits apoptosis via the AMP-activated protein kinase–silent mating type information regulation 2 homologue 1–PPARγ co-activator-1α axis in rat mesangial cells under high-dose glucosamine

Pathophysiology of the Diabetic Kidney

AS101 Prevents Diabetic Nephropathy Progression and Mesangial Cell Dysfunction: Regulation of the AKT Downstream Pathway

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