Transactivation of the Epidermal Growth Factor Receptor by Angiotensin II in Glomerular Podocytes

Flannery, Patrick J.; Spurney, Robert F.

doi:10.1159/000092196

Cited by 32 publications

(22 citation statements)

References 95 publications

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“…Podocytes express AT1- and probably AT2-receptors [10]. ANG II transactivates the epidermal growth factor receptor in podocytes by activation of AT1- and AT2-receptors [11]. This is caused by ANG II-induced processing of heparin-binding-epidermal growth factor (HB-EGF) from its precursor [11].…”

Section: Podocyte Dysfunction In Diabetes As Revealed In Experimentalmentioning

confidence: 99%

“…ANG II transactivates the epidermal growth factor receptor in podocytes by activation of AT1- and AT2-receptors [11]. This is caused by ANG II-induced processing of heparin-binding-epidermal growth factor (HB-EGF) from its precursor [11]. Moreover, ANG II-stimulated release of HB-EGF activates in a paracrine fashion MAP kinase activity in adjacent cells [11].…”

Section: Podocyte Dysfunction In Diabetes As Revealed In Experimentalmentioning

confidence: 99%

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Cellular and Molecular Mechanisms of Proteinuria in Diabetic Nephropathy

2007

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One of the earliest clinically detectable abnormalities in diabetic nephropathy is microalbuminuria that eventually progresses to proteinuria. The degree of proteinuria correlates with the progression of glomerulosclerosis and tubulointerstitial fibrosis. In the glomerulus, a typical podocytopathy develops that participates in the initiation of glomerulosclerosis and the accelerated plasma protein leakage across the glomerular basement membrane (GBM) into Bowman’s space. Downstream into the tubular compartment, the proteinuria induces proinflammatory and profibrogenetic injury in tubular cells which can facilitate the development of interstitial fibrosis and tubular atrophy. It has long been held that hemodynamic changes and the loss of negatively charged proteoglycans in the GBM are important mediators of proteinuria. More recently, biopsy studies in humans with diabetic kidney disease have provided strong evidence that podocytes are injured very early in the course of nephropathy. This podocytopathy – which is characterized by decreased podocyte number and/or density, GBM thickening and altered matrix composition, and foot process effacement – correlates closely with the development and progression of albuminuria. Components of the diabetic milieu (high glucose, accumulation of glycated proteins, high intrarenal angiotensin II (ANG II), and hypertension-induced mechanical stress) result in activation of cytokine systems, the most important of which are transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor-A (VEGF-A). ANG II-stimulated podocyte-derived VEGF, through a novel autocrine signaling loop, appears to be a major cause of nephrin downregulation and the development of proteinuria. Nephrin is an important protein of the slit diaphragm with anti-apoptotic signaling properties. TGF-β1 causes podocyte apoptosis and an increase in extracellular matrix deposition. As a consequence, the denuded GBM adheres to Bowman’s capsule initiating the development of glomerulosclerosis. Good control of hyperglycemia and hypertension and maximal inhibition of ANG II are essential steps in preventing the development and progression of diabetic nephropathy.

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Section: Podocyte Dysfunction In Diabetes As Revealed In Experimentalmentioning

confidence: 99%

Section: Podocyte Dysfunction In Diabetes As Revealed In Experimentalmentioning

confidence: 99%

Cellular and Molecular Mechanisms of Proteinuria in Diabetic Nephropathy

2007

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“…Phosphorylation of ERK was induced by some pathogenetic events, including high glucose and angiotensin II in cultured podocytes [30,31,32]. Activation of ERK resulted in the oversecretion of vascular endothelial growth factor and production of matrix metalloproteinase 9 in podocytes [30, 31].…”

Section: Discussionmentioning

confidence: 99%

Pravastatin Inhibits Carboxymethyllysine-Induced Monocyte Chemoattractant Protein 1 Expression in Podocytes via Prevention of Signalling Events

Qian

et al. 2007

Nephron Exp Nephrol

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Background: Up-regulation of local monocyte chemoattractant protein 1 (MCP-1) production is involved in glomerular damage through macrophage recruitment and activation in diabetic nephropathy. Advanced glycation end-products induced chemokine production in cultured mesangial cells and podocytes. Statins prevented recruitment of macrophages to the glomeruli, suggesting that statins may have the ability of anti-inflammation. In the present studies, we investigated the effects of pravastatin in the carboxymethyllysine (CML)-induced MCP-1 expression in mouse differentiated podocytes. Methods: MCP-1 gene and protein expressions were examined using RT-PCR and ELISA. Dichlorofluorescein-sensitive intracellular reactive oxygen species (ROS) generation was measured by confocal microscopy. Activation of extracellular signal-regulated kinase (ERK), nuclear factor (NF) ĸB and Sp1 were studied using Western blotting and immunocytochemistry. Results: MCP-1 was induced by CML in a time- and dose-dependent manner. CML-induced MCP-1 mRNA and protein production were inhibited by 0.1 or 1 mM pravastatin. CML rapidly generated intracellular ROS in podocytes.Pravastatin did not have any ability of blocking ROS generation. Phosphorylated ERK was found in podocytes incubated with CML and was prevented by pravastatin in a dose-dependent manner. Both Western blotting and immunocytochemistry results suggested that pretreatment of podocytes with pravastatin prevented the CML-induced NF-ĸB and Sp1 translocation. Conclusion: These results suggest that pravastatin prevents CML to induce MCP-1 expression in podocytes via modulation of the intracellular ERK/NF-ĸB and Sp1 signalling pathway.

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“…One is the AT1R-dependent activation of calcineurin (40). Furthermore, AT1R signaling causes transactivation of the EGF receptor (EGFR) in podocytes (22). AT1R-EGFR interactions also activate downstream serine/threonine kinases such as the MAPK Regulation of TRPC6 ion channels in podocytes 245 245 pathway in a process that is known to require an increase in cytosolic [Ca 2+ ] (34).…”

Section: Interaction Of Trpc6 With Other Sd Proteins Of the Filtratiomentioning

confidence: 99%

Regulation of TRPC6 ion channels in podocytes — Implications for focal segmental glomerulosclerosis and acquired forms of proteinuric diseases

Szabó¹,

Ambrus²,

Zákány³

et al. 2015

Acta Physiologica Hungarica

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The glomerular filtration barrier is a highly specialized tri-layer structure with unique functional properties. Podocyte dysfunction and cytoskeletal disorganization leads to disruption of the slit diaphragma, and proteinuria. Inflammatory diseases involving the kidney as well as inherited podocytopathies or diabetic nephropathy cause injury of the podocyte network. Focal segmental glomerulosclerosis (FSGS) is a pathologic entity that is a common cause of nephrotic syndrome with severe proteinuria in both adults and children. Several causative genes have been identified in the pathogenesis of FSGS. Mutations of the transient receptor potential canonical-6 (TRPC6), a non-selective cation channel that is directly activated by diacylglycerol (DAG), cause a particularly aggressive form of FSGS. Angiotensin II, acting through its AT1 receptor, plays a critical role in generation of proteinuria and progression of kidney injury in a number of kidney diseases, including FSGS. Mounting evidence suggest the central role of TRPC6 and perhaps other TRPC channels in the pathogenesis of FSGS as well as of acquired forms of proteinuria such as diabetic nephropathy or hypertension. Identification of signaling pathways downstream of TRPC6 may provide novel targets for the treatment of proteinuria and prevent progression of podocyte injury.

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Transactivation of the Epidermal Growth Factor Receptor by Angiotensin II in Glomerular Podocytes

Cited by 32 publications

References 95 publications

Cellular and Molecular Mechanisms of Proteinuria in Diabetic Nephropathy

Cellular and Molecular Mechanisms of Proteinuria in Diabetic Nephropathy

Pravastatin Inhibits Carboxymethyllysine-Induced Monocyte Chemoattractant Protein 1 Expression in Podocytes via Prevention of Signalling Events

Regulation of TRPC6 ion channels in podocytes — Implications for focal segmental glomerulosclerosis and acquired forms of proteinuric diseases

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