Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation

Huang, Songming; Zhang, Aihua; Ding, Guofu; Chen, Ronghua

doi:10.1152/ajprenal.90428.2008

Cited by 81 publications

(92 citation statements)

References 48 publications

(72 reference statements)

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“…These results support the view that the mechanism of action of Aldo on myofibroblast proliferation is mediated by MR and requires both EGF secretion and EGFR activation. These findings constitute new evidence for Aldo interaction with peptide hormone signaling, as previously shown by Aldo-stimulated mesangial cell proliferation (12) and for cardiac Na/H exchanger expression (6). Our findings confirm that Aldo leads to enhanced EGFR expression via interaction with the EFGR promoter, as previously shown by Grossmann et al (10) ANG II-inducing TGF-␤ and its downstream mediators resulting in matrix accumulation, inflammation, and apoptosis (24), and Aldo-inducing EGF, promoting myofibroblast and fibroblast growth and proliferation.…”

Section: Discussionsupporting

confidence: 82%

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Aldosterone induces myofibroblast EGF secretion to regulate epithelial colonic permeability

Miró

Pérez-Bosque

Maijó

et al. 2013

American Journal of Physiology-Cell Physiology

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Miró L, Pérez-Bosque A, Maijó M, Amat C, Naftalin RJ, Moretó M. Aldosterone induces myofibroblast EGF secretion to regulate epithelial colonic permeability. Am J Physiol Cell Physiol 304: C918-C926, 2013. First published March 6, 2013; doi:10.1152 doi:10. /ajpcell.00292.2012 show that raised aldosterone (Aldo) during low-Na adaptation regulates the growth of pericryptal myofibroblasts and reduces the permeability of the colonic epithelium. The aim of this study was to reproduce in vitro the in vivo condition of increased Aldo using human CCD-18Co myofibroblasts and T84 colonic epithelial cells to measure myofibroblast and epithelial proliferation and the expression of intercellular junction proteins. Proliferation was quantified by measuring 5-bromo-2=-deoxyuridine incorporation. The myofibroblast expression of EGF, VEGFa, and transforming growth factor-␤1 (TGF-␤1) was measured by real-time PCR and the expression of junctional complex proteins by Western blot. Aldo stimulated the proliferation of myofibroblasts by 70% (P Ͻ 0.05) and increased EGF mRNA expression by 30% (P Ͻ 0.05) without affecting VEGFa and TGF-␤1. EGF concentration in the incubation medium increased by 30% (P Ͻ 0.05) 24 h after Aldo addition, and these effects were prevented by the addition of spironolactone. Myofibroblast proliferation in response to Aldo was mediated by EGF receptor (EGFR) and involved both MAPKK and phosphatidylinositol 3-kinase pathways. When T84 cells were incubated with medium from myofibroblasts stimulated with Aldo (conditioned medium), the expression of ␤-catenin and claudin IV was increased by 30% (P Ͻ 0.05) and proliferation by 40% (P Ͻ 0.05). T84 proliferation decreased when ␣-EGF, or the EGFR antagonist AG1478, was present. Results in vivo indicate that rats fed a low-salt diet showed an increased expression of EGF and EGFR in the colonic mucosa. These results support the view that changes in colonic permeability during low-Na adaptation are mediated by the EGF secreted by myofibroblasts in response to raised Aldo. aldosterone; EGF; proliferation THE CRYPTS IN THE DESCENDING colon can absorb fluid despite a high hydraulic resistance in the lumen. The capacity to absorb a hypertonic absorbate requires Na pump activity and a physical barrier to Na movement from the pericryptal space into the submucosa and pericryptal capillaries to maintain a high osmotic pressure gradient across the crypt mucosa (19). This physical barrier is called the pericryptal sheath and is made up of a network of myofibroblast-like cells and the extracellular matrix surrounding the colonic crypts (13,19,22).Low-Na intake activates the renin-angiotensin-aldosterone system (RAAS), which increases both angiotensin II (ANG II) and aldosterone (Aldo) plasma concentration. Activation of the RAAS increases colonic fluid and Na absorption (31). These effects are partly due to the upregulation of the epithelial sodium channel (ENaC) and changes in the barrier function of the pericryptal sheath, as has been shown in both rat and mouse descending colonic...

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Section: Discussionsupporting

confidence: 82%

“…Aldo stimulates proliferation in different cell types, such as renal M1-CCD (14) and mesangial cells (12). In all cases, preincubation with the MAPKK inhibitor PD98059 blocked proliferation.…”

Section: Discussionmentioning

confidence: 89%

Aldosterone induces myofibroblast EGF secretion to regulate epithelial colonic permeability

Miró

Pérez-Bosque

Maijó

et al. 2013

American Journal of Physiology-Cell Physiology

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“…22 Kidney ROS production was measured in frozen kidney sections embedded in Optimal Cutting Temperature embedding medium,. Sections were covered with 10 mol/L 2=,7=-dichlorofluorescein diacetate and incubated in the dark at 37°C for 30 minutes.…”

Section: Ros Productionmentioning

confidence: 99%

Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

Zhu

Huang

Yuan

et al. 2011

The American Journal of Pathology

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107

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Aldosterone (Aldo) causes podocyte damage by an unknown mechanism. We examined the role of mitochondrial dysfunction (MtD) in Aldo-treated podocytes in vitro and in vivo. Exposure of podocytes to Aldo reduced nephrin expression dose dependently, accompanied by increased production of reactive oxygen species (ROS). The ROS generation and podocyte damage were abolished by the mitochondrial (mt) respiratory chain complex I inhibitor rotenone. Pronounced MtD, including reduced mt membrane potential, ATP levels, and mtDNA copy number were seen in Aldo-treated podocytes and in the glomeruli of Aldo-infused mice. The mineralocorticoid receptor antagonist eplerenone significantly inhibited Aldo-induced MtD. The MtD was associated with higher levels of ROS, reduction in the activity of complexes I, III, and IV, and expression of the peroxisome proliferator-activated receptor-␥ (PPAR␥) coactivator-1␣ and mt transcription factor A. Both the PPAR␥ agonist rosiglitazone and PPAR␥ overexpression protected against podocyte injury by preventing MtD and oxidative stress, as evidenced by reduced ROS production, by maintenance of mt morphology, by restoration of mtDNA copy number, by decrease in mt membrane potential loss, and by recovery of mt electron transport function. The protective effect of rosiglitazone was abrogated by the specific PPAR␥ small interference RNA, but not a control small interference RNA. We conclude that MtD is involved in Aldo-induced podocyte injury, and that the PPAR␥ agonist rosiglitazone may protect podocytes from this injury by The mineralocorticoid aldosterone (Aldo) is a key component of the renin-angiotensin-aldosterone system and is increasingly recognized as an important player in the development and progression of kidney disease. Patients with chronic kidney disease have markedly elevated plasma Aldo concentrations. Animal studies suggest that Aldo is a pathogenic factor in renal injury in the remnant kidney of hypertensive rats, 1 and in renal fibrosis. Moreover, exogenous infusion of Aldo reverses the renoprotective effects of angiotensin-converting enzyme inhibitors in hypertensive remnant kidney rats, and in stroke-prone, spontaneously hypertensive rats. 2 In vitro studies show that Aldo exerts a direct deleterious influence on kidney cells, including podocytes, 3-5 mesangial cells, proximal tubular epithelial cells, 6 and fibroblasts. In particular, Aldo causes podocyte injury in vivo and in vitro, and Aldo blockade is therapeutic in renal injury. 5,[7][8][9] However, the underlying mechanism for Aldoinduced injury in the kidney (in general) and in the podocytes (in particular) is not well understood.Podocytes are terminally differentiated, high-energy required cells that have lost mitotic activity, and typically do not proliferate after injury. 10 Mitochondria (mt) dysfunction (MtD) is involved in several diseases and progressive disease processes, including glomerulosclerosis, in which podocyte injury is a crucial event in sclerosis formation. 11,12 We hypothesized that preserving mt func...

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“…Chronic infusion of aldosterone increased renal ROS formation via NADPH oxidase activation (25,31,32). Nishiyama et al (25) showed that aldosterone/salt-induced renal injury was associated with increased thiobarbituric acid-reactive substance (TBARS) content, a marker of ROS production, and mRNA levels of NADPH oxidase components, p22phox, Nox-4, and gp91phox, in renal cortical tissues.…”

Section: Aldosterone/mr and Reactive Oxygen Species (Ros) In The Kidneymentioning

confidence: 99%

“…Recent studies have shown that aldosterone induces mesangial cell apoptosis and that the administration of an antioxidant or a MR antagonist attenuates the proapoptotic effects of aldosterone (36). In addition, Huang et al (32) showed that aldosterone dosedependently increased ROS formation in mesangial cells, which was blocked by an MR antagonist, an inhibitor of complex I of the mitochondrial respiratory chain, or an inhibitor of NADPH oxidase. These findings suggest that mitochondria and NADPH oxidase are the major sources of aldosterone-dependent renal ROS production.…”

Section: Aldosterone/mr and Reactive Oxygen Species (Ros) In The Kidneymentioning

confidence: 99%

Pathophysiological Roles of Aldosterone and Mineralocorticoid Receptor in the Kidney

et al. 2011

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Abstract. Aldosterone, a steroid hormone, has traditionally been viewed as a key regulator of fluid and electrolyte homeostasis, as well as blood pressure, through the activation of mineralocorticoid receptor (MR). However, a number of studies performed in the last decade have revealed an important role of aldosterone/MR in the pathogenesis of renal injury. Aldosterone/MR-induced renal tissue injury is associated with increased renal inflammation and oxidative stress, fibrosis, mesangial cell proliferation, and podocyte injury, probably through genomic and non-genomic pathways. However, our preliminary data have indicated that acute administration of aldosterone or a selective MR antagonist, eplerenone, does not change blood pressure, heart rate, or renal blood flow. These data suggest that aldosterone/MR induces renal injury through mechanisms that are independent of acute changes in systemic and renal hemodynamics. In this review, we will briefly summarize the roles of aldosterone/MR in the pathogenesis of renal injury, focusing on the underlying mechanisms that are independent of systemic and renal hemodynamic changes.

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Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation

Cited by 81 publications

References 48 publications

Aldosterone induces myofibroblast EGF secretion to regulate epithelial colonic permeability

Aldosterone induces myofibroblast EGF secretion to regulate epithelial colonic permeability

Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

Pathophysiological Roles of Aldosterone and Mineralocorticoid Receptor in the Kidney

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