Enhanced TGF-b/Smad signaling in the early stage of diabetic nephropathy is independent of the AT1a receptor

Okazaki, Yuko; Yamasaki, Yasushi; Uchida, Haruhito A.; Okamoto, Kazunori; Satoh, Minoru; Maruyama, Kouichi; Maeshima, Yohei; Sugiyama, Hiroshi; Sugaya, Takeshi; Kashihara, Naoki; Makino, Hírofumi

doi:10.1007/s10157-006-0456-1

Cited by 18 publications

(13 citation statements)

References 44 publications

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“…In a previous study, TGF‐β expression in the glomeruli was increased significantly not only in diabetic AT 1a +/+ mice, but also in dietetic AT 1a −/− mice and AT 1a receptor activation was demonstrated to mediate approximately 80% of the renal effects of AngII 33 . Whether increases in TGF‐β are mediated by AT 1 receptors or AT 1 receptor‐independent mechanisms remains unknown 34 …”

Section: Discussionmentioning

confidence: 94%

Angiotensin AT₁ receptor activation mediates high glucose‐induced epithelial–mesenchymal transition in renal proximal tubular cells

Zhou

Xue

Yuan

et al. 2010

Clin Exp Pharma Physio

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SUMMARY1. Renal tubular epithelial cells can undergo epithelial to mesenchymal transition (EMT) under hyperglycaemic conditions, which is associated with renal interstitial fibrosis. Activation of the renin-angiotensin system (RAS) is involved in diabetic nephropathy. The present study investigated the positive role of angiotensin AT 1 receptors in high glucose-induced EMT in cultured tubular epithelial cells.2. A rat kidney proximal tubular epithelial cell line (NRK-52E) was used in the present study. Levels of EMT makers, namely E-cadherin and vimentin, were estimated using fluorescence immunocytochemistry, mRNA levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and AT 1 receptors were determined by real-time polymerase chain reaction, protein levels of E-cadherin, vimentin, fibronectin, matrix metallopeptidase (MMP)-9 and phosphorylated extracellular signal-regulated kinase (ERK) 1 ⁄ 2 were analysed by western blotting and the concentrations of angiotensin (Ang) II and transforming growth factor (TGF)-b1 in the culture medium were determined by enzyme immunoassay and ELISA.3. High glucose (30 mmol ⁄ L) induced EMT and increased the synthesis of fibronectin and MMP-9. Furthermore, high glucose increased AGT, ACE and AT 1 receptor mRNA levels, as well as AngII and TGF-b1 concentrations in the culture medium and ERK1 ⁄ 2 phosphorylation. Pretreatment of cells for 15 min with the AT 1 receptor antagonist losartan (10 )5 mol ⁄ L) attenuated high glucose-induced increases in TGF-b1 and ERK1⁄ 2 phosphorylation and reduced EMT, as well as the consequent synthesis of fibronectin and MMP-9. 4. The results of the present study suggest that the activated local RAS mediates high glucose-induced EMT. By activating AT 1 receptors and stimulating TGF-b1 synthesis, the elevated local RAS participates in high glucose-induced EMT and increased extracellular matrix secretion.

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Section: Discussionmentioning

confidence: 94%

Angiotensin AT₁ receptor activation mediates high glucose‐induced epithelial–mesenchymal transition in renal proximal tubular cells

Zhou

Xue

Yuan

et al. 2010

Clin Exp Pharma Physio

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“…As hyperglycaemia and HNE can trigger multiple signalling pathways [22,[26][27][28][29], in order to confirm the direct effect of WNT activation on renal fibrogenesis in diabetic nephropathy, primary HRPTC were exposed to WNT3A-conditioned medium (WCM); plain L cell conditioned medium (LCM) was used as a control. As shown by western blot analysis, WCM increased cytosolic and nuclear β-catenin levels significantly compared with LCM ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

et al. 2011

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Aims/hypothesis The wingless-type MMTV integration site (WNT) pathway mediates multiple physiological and pathological processes, such as inflammation, angiogenesis and fibrosis. The aim of this study was to investigate whether canonical WNT signalling plays a role in the pathogenesis of diabetic nephropathy. Methods Expression of WNT ligands and frizzled receptors in the canonical WNT pathway in the kidney was compared at the mRNA level using real-time RT-PCR between Akita mice, streptozotocin-induced diabetic rats and db/db mice and their respective non-diabetic controls. Renal function was evaluated by measuring the urine albumin excretion. Human renal proximal tubular epithelial cells were treated with high-glucose medium and 4-hydroxynonenal (HNE). Levels of β-catenin, connective tissue growth factor and fibronectin were determined by western blot analysis. Results Some of the WNT ligands and frizzled receptors showed increased mRNA levels in the kidneys of Akita mice, streptozotocin-induced diabetic rats and db/db mice compared with their non-diabetic controls. Renal levels of β-catenin and WNT proteins were upregulated in these diabetic models. Lowering the blood glucose levels by insulin attenuated the activation of WNT signalling in the kidneys of Akita mice. In cultured human renal proximal tubular epithelial cells, both high glucose and HNE activated WNT signalling. Inhibition of WNT signalling with a monoclonal antibody blocking LDL-receptor-related protein 6 ameliorated renal inflammation and fibrosis and reduced proteinuria in Akita mice. Conclusions/interpretation The WNT pathway is activated in the kidneys of models of both type 1 and 2 diabetes. Dysregulation of the WNT pathway in diabetes represents a new pathogenic mechanism of diabetic nephropathy and renders a new therapeutic target.

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“…Increased GCR sensitivity can be considered as an indicator of excessive activity of GC which is a plausible contributor to obesity and insulin resistance. FFA induces the over-expression of TGFBRII as noted in diabetic kidney disease [100] and it increases the expressions of proto-oncogenes and SMAD3 in TGFB signalling process [101]. TGFB induces as well as gets activated by ROS intermediates [102], [65].…”

Section: Discussionmentioning

confidence: 99%

Expression-Based Network Biology Identifies Alteration in Key Regulatory Pathways of Type 2 Diabetes and Associated Risk/Complications

et al. 2009

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Type 2 diabetes mellitus (T2D) is a multifactorial and genetically heterogeneous disease which leads to impaired glucose homeostasis and insulin resistance. The advanced form of disease causes acute cardiovascular, renal, neurological and microvascular complications. Thus there is a constant need to discover new and efficient treatment against the disease by seeking to uncover various novel alternate signalling mechanisms that can lead to diabetes and its associated complications. The present study allows detection of molecular targets by unravelling their role in altered biological pathways during diabetes and its associated risk factors and complications. We have used an integrated functional networks concept by merging co-expression network and interaction network to detect the transcriptionally altered pathways and regulations involved in the disease. Our analysis reports four novel significant networks which could lead to the development of diabetes and other associated dysfunctions. (a) The first network illustrates the up regulation of TGFBRII facilitating oxidative stress and causing the expression of early transcription genes via MAPK pathway leading to cardiovascular and kidney related complications. (b) The second network demonstrates novel interactions between GAPDH and inflammatory and proliferation candidate genes i.e., SUMO4 and EGFR indicating a new link between obesity and diabetes. (c) The third network portrays unique interactions PTPN1 with EGFR and CAV1 which could lead to an impaired vascular function in diabetic nephropathy condition. (d) Lastly, from our fourth network we have inferred that the interaction of β-catenin with CDH5 and TGFBR1 through Smad molecules could contribute to endothelial dysfunction. A probability of emergence of kidney complication might be suggested in T2D condition. An experimental investigation on this aspect may further provide more decisive observation in drug target identification and better understanding of the pathophysiology of T2D and its complications.

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Enhanced TGF-b/Smad signaling in the early stage of diabetic nephropathy is independent of the AT1a receptor

Abstract: Our results suggest that the complete blockade of the AT1a-mediated pathway has a minimal effect on the enhanced TGF-beta/Smad signaling in the early stage of DN, at least in the AT1a(-/-) model.

Cited by 18 publications

References 44 publications

Angiotensin AT₁ receptor activation mediates high glucose‐induced epithelial–mesenchymal transition in renal proximal tubular cells

Angiotensin AT₁ receptor activation mediates high glucose‐induced epithelial–mesenchymal transition in renal proximal tubular cells

Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

Expression-Based Network Biology Identifies Alteration in Key Regulatory Pathways of Type 2 Diabetes and Associated Risk/Complications

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Enhanced TGF-b/Smad signaling in the early stage of diabetic nephropathy is independent of the AT1a receptor

Abstract: Our results suggest that the complete blockade of the AT1a-mediated pathway has a minimal effect on the enhanced TGF-beta/Smad signaling in the early stage of DN, at least in the AT1a(-/-) model.

Cited by 18 publications

References 44 publications

Angiotensin AT1 receptor activation mediates high glucose‐induced epithelial–mesenchymal transition in renal proximal tubular cells

Angiotensin AT1 receptor activation mediates high glucose‐induced epithelial–mesenchymal transition in renal proximal tubular cells

Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

Expression-Based Network Biology Identifies Alteration in Key Regulatory Pathways of Type 2 Diabetes and Associated Risk/Complications

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Angiotensin AT₁ receptor activation mediates high glucose‐induced epithelial–mesenchymal transition in renal proximal tubular cells

Angiotensin AT₁ receptor activation mediates high glucose‐induced epithelial–mesenchymal transition in renal proximal tubular cells