Molecular mechanisms of glucose action on angiotensinogen gene expression in rat proximal tubular cells

Zhang, Shao-LING; Filep, János G.; Hohman, Thomas C.; Tang, Shiow‐Shih; Ingelfinger, Julie R.; Chan, John S.D.

doi:10.1046/j.1523-1755.1999.00271.x

Cited by 112 publications

(87 citation statements)

References 31 publications

(9 reference statements)

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“…8). High blood glucose has been shown to increase AngII production (48), and this together with the fact that AngII can increase TGF-␤1 and vice versa (44) suggests that RAS-affecting drugs may also modulate TGF-␤ production. This presents an important linking factor for the renoprotective effects of RAS-affecting drugs as well as the potential renoprotective effects of TGF-␤ blocking agents in the treatment of diabetes-induced albuminuria.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a Role of Transforming Growth Factor (TGF)-β1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy

et al. 2007

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Transforming growth factor-␤ (TGF-␤) has previously been implicated in the progression of diabetic nephropathy, including the onset of fibrosis and albuminuria. Here we report for the first time the use of a high-affinity TGF-␤1 binding molecule, the soluble human TGF-␤ type II receptor (sT␤RII.Fc), in the treatment of diabetic nephropathy in 12-week streptozotocin-induced diabetic Sprague-Dawley rats. In vitro studies using immortalized rat proximal tubule cells revealed that 50 pmol/l TGF-␤1 disrupted albumin uptake (P < 0.001 vs. control), an inhibition significantly reversed by the use of the sT␤RII.Fc (1,200 pmol/l). In vivo studies demonstrated that treatment with sT␤RII.Fc reduced urinary albumin excretion by 36% at 4 weeks, 59% at 8 weeks (P < 0.001), and 45% at 12 weeks (P < 0.01 for diabetic vs. treated). This was correlated with an increase in megalin expression (P < 0.05 for diabetic vs. treated) and a reduction in collagen IV expression following sT␤RII.Fc treatment (P < 0.001 for diabetic vs. treated). These changes occurred independently of changes in blood glucose levels. This study demonstrates that the sT␤RII.Fc is a potential new agent for the treatment of fibrosis and albuminuria in diabetic nephropathy and may reduce albuminuria by reducing TGF-␤1-induced disruptions of renal proximal tubule cell uptake of albumin. Diabetes 56:380 -388, 2007

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Section: Discussionmentioning

confidence: 99%

Evidence for a Role of Transforming Growth Factor (TGF)-β1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy

et al. 2007

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“…Extracellular matrix (ECM) accumulation is central to the glomerular and interstitial lesions that ultimately culminate in diabetic nephropathy [3,4] and studies have suggested that the renin-angiotensin-system (RAS) has an important influence on renal ECM dynamics [4]. Glucose could increase mesangial cell angiotensin II production [5]. Angiotensin II upregulates TGF-β receptor expression in cultured mesangial cells, thus stimulating ECM production [6].…”

Section: :82-88]mentioning

confidence: 99%

Juxtaglomerular apparatus T-cell infiltration affects glomerular structure in Type 1 diabetic patients

2004

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Aims/hypothesis. Type 1 diabetes is an autoimmune disorder associated with T-cell mediated injury to multiple endocrine tissues. T-cell infiltration of the juxtaglomerular apparatus could be associated with changes in local renin angiotensin system activity and, thus, with changes in the renal microenvironment. We examined the frequency of juxtaglomerular apparatus T-cell infiltration early in Type 1 diabetes and tested whether this is associated with renal structure and function. Methods. We classified 89 Type 1 diabetic patients by immunohistochemical analysis as either juxtaglomerular apparatus T-cell positive (n=37) or T-cell negative (n=38). Borderline cases (n=14) were not considered further.Results. T-cell positive patients had a shorter duration of diabetes (6.7±2.5 years) than T-cell negative patients (9.2±5.0 years, p=0.011) and lower albumin excretion rate, but they had a similar glomerular filtration rate and blood pressure. Renal biopsy morphometric analysis showed similar glomerular basement membrane width and mesangial fractional volume in these two groups. However, glomerular capillary surface density (p=0.0012) and filtration surface per glomerulus (p=0.0155) were greater in the T-cell positive patients. Conclusion/Interpretation. Increased filtration surface per glomerulus could be associated with glomerular filtration rate preservation in diabetes. Thus, juxtaglomerular apparatus immunologic injury in Type 1 diabetes patients could delay the clinical consequences of diabetic nephropathy. [Diabetologia (2004) Minneapolis, MN 55455, USA E-mail: mauer002@umn.edu Abbreviations: ECM, Extracellular matrix; RAS, renin-angiotensin-system; JGA, juxtaglomerular apparatus; NHDN, natural history of diabetic nephropathy; IP, immunoperoxidase; GV, mean glomerular volume; TGF-B, transforming growth factor-B; Vv(Mes/glom), mesangial fractional volume per glomerulus; GBM, glomerular basement membrane; Sv(PGBM/glom), surface density of the peripheral glomerular capillary perglomerulus ; TFS, total filtration surface per glomerulus; Vv(Int/cortex), fractional volume of renal cortical interstitium.

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“…We have reported that high concentrations of glucose (25 mM) stimulate the expression of angiotensinogen protein and mRNA in rat immortalized RPTCs (IRPTCs) (Zhang et al 1999b(Zhang et al , 2000. RAS blockade and stable transfection of antisense rat angiotensinogen cDNA inhibited the effect of high glucose concentrations on the expression of angiotensinogen protein and mRNA, the expression of transforming growth factor-1 mRNA and the induction of IRPTC hypertrophy (Zhang et al , 2002c.…”

Section: Introductionmentioning

confidence: 99%

Reactive oxygen species blockade and action of insulin on expression of angiotensinogen gene in proximal tubular cells

Hsieh¹,

Fustier²,

Wei³

et al. 2004

Journal of Endocrinology

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We reported previously that insulin inhibits the stimulatory effect of high glucose on the expression of angiotensinogen (ANG) gene in both rat immortalized renal proximal tubular cells (IRPTCs) and non-diabetic rat renal proximal tubular cells (RPTCs), but has no effect in diabetic rat RPTCs. In the present study we investigated whether hyperglycaemia-induced resistance to the insulininduced inhibition of expression of the ANG gene is mediated via the generation of reactive oxygen species (ROS) in RPTCs. Rat IRPTCs were cultured for 2 weeks in high-glucose (25 mM) or normal-glucose (5 mM) medium plus angiotensin II (Ang II) with or without a superoxide scavenger (tiron), or inhibitors of: NADPH oxidase (diphenylene iodinium, DPI), Ang II type 1 and 2 receptors (losartan and PD123319), angiotensinconverting enzyme (perindopril), protein kinase C (GF 109203X), or glutamine:fructose-6-phosphate aminotransferase (azaserine). Cellular generation of ROS, and ANG and renin mRNA levels were assessed by lucigenin assay and specific reverse transcriptase-PCR respectively. Phosphorylation of p44/42 mitogen-activated protein kinase (p44/42 MAPK) was evaluated by western blotting. Prolonged exposure of IRPTCs to high concentrations of glucose or Ang II evoked generation of ROS and resistance to the insulin-induced inhibition of expression of the ANG gene and of p44/42 MAPK phosphorylation. Co-incubation of IRPTCs with tiron, DPI, losartan, PD123319, perindopril, GF 109203X or azaserine prevented ROS generation, restoring the inhibitory action of insulin on ANG gene expression and on p44/42 MAPK phosphorylation. In conclusion, our studies demonstrate that blockade of both ROS generation and activation of the intrarenal renin-angiotensin system improves the inhibitory action of insulin on ANG gene expression in IRPTCs in conditions of high glucose.

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Molecular mechanisms of glucose action on angiotensinogen gene expression in rat proximal tubular cells

Abstract: These studies suggest that the stimulatory effect of a high level of D(+)-glucose (25 mM) on the expression of the ANG gene in IRPTCs is mediated, at least in part, via the de novo synthesis of DAG, an activator of PKC signal transduction pathway.

Cited by 112 publications

References 31 publications

Evidence for a Role of Transforming Growth Factor (TGF)-β1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy

Evidence for a Role of Transforming Growth Factor (TGF)-β1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy

Juxtaglomerular apparatus T-cell infiltration affects glomerular structure in Type 1 diabetic patients

Reactive oxygen species blockade and action of insulin on expression of angiotensinogen gene in proximal tubular cells

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