Direct Aldosterone Action as a Profibrotic Factor via ROS-Mediated SGK1 in Peritoneal Fibroblasts

Yamahara, Hideki; Kishimoto, Noriko; Nakata, Midori; Okazaki, Akiko; Kimura, Takayasu; Sonomura, Kazuhiro; Matsuoka, Eiko; Shiotsu, Yayoi; Adachi, Takaomi; Matsubara, Hiroaki; Iwasaka, Toshiji; Mori, Yoshihide

doi:10.1159/000225379

Cited by 20 publications

(17 citation statements)

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“…In vitro studies have suggested that Aldo could directly promote fibrotic responses, enhance the production of transforming growth factor TGF-β1, PAI-1 and connective tissue growth factor [21,22], and induce EMT in cultured kidney tubular cells, resulting in their transformation into myofibroblasts [23]. These findings suggest that Aldo may lead to matrix accumulation in kidney.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin Attenuates Aldosterone-Induced Tubulointerstitial Inflammation and Fibrosis

Wang

Ding

Zhang

et al. 2015

Cell Physiol Biochem

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Background/Aim: Aldosterone (Aldo), a mediator of kidney fibrosis, is implicated in the pathogenesis of chronic kidney diseases (CKD). The aim of this study was to evaluate the regulatory role of rapamycin (Rap) in Aldo-induced tubulointerstitial inflammation and fibrosis. Methods: Uninephrectomized, Sprague-Dawley rats were given 1% NaCl (salt) to drink and were randomized to receive treatment for 28 days as follows: vehicle infusion (control), 0.75 μg/h Aldo subcutaneous infusion, or Aldo infusion plus 1 mg/kg/day of Rap by intraperitoneal injection. The effect of Rap on Aldo-induced fibrosis and renal inflammation was investigated using Masson's technique, immunohistochemistry, and western blotting. The effects of Rap on the Aldo-induced epithelial-mesenchymal transition (EMT) process and on TNF-α mRNA expression and secretion in cultured HK-2 cells were investigated by immunofluorescent staining, western blot, qRT-PCR and ELISA. Results: An in vivo study indicated that signaling by the mammalian target of Rap (mTOR) was activated in rats in the Aldo group compared to controls, as indicated by up-regulated expression of p-mTOR and p-S6K. In addition, the inflammatory response increased, as evidenced by increases in inflammatory markers (MCP-1, ICAM-1, F4/80), and the accumulation of extracellular matrix (ECM), as indicated by increased collagen I and fibronectin expression and pro-fibrogenic gene (PAI-1 and TGF-β1) expression. These changes were attenuated by Rap treatment. An in vitro study showed that Rap significantly suppressed the Aldo-induced EMT process and TNF-α mRNA expression and secretion in cultured HK-2 cells. Conclusions: Rap can ameliorate tubulointerstitial inflammation and fibrosis by blocking mTOR signaling. Tubular cells may be a major cell type involved in this physiologic process.

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Section: Discussionmentioning

confidence: 99%

Rapamycin Attenuates Aldosterone-Induced Tubulointerstitial Inflammation and Fibrosis

Wang

Ding

Zhang

et al. 2015

Cell Physiol Biochem

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“…Mineralocorticoids stimulate vascular [10,23,24,29,30,31], cardiac [8,24,29,32,33,34,35,36,37,38,39,40], renal [24,26,36,41,42,43], peritoneal [14,17] and pancreatic [44] fibrosis.…”

Section: Effect Of Mineralocorticoids On Inflammation and Fibrosismentioning

confidence: 99%

“…Specific emphasis will be placed on the role of the serum- and glucocorticoid-inducible kinase 1 (SGK1) in the mineralocorticoid action on inflammation and fibrosis. The reader is encouraged to consult earlier, more extensive reviews on mineralocorticoids and inflammation as well as tissue fibrosis [8,9,10,11,12,13,14,15,16,17]. …”

Section: Introductionmentioning

confidence: 99%

Mineralocorticoid and SGK1-Sensitive Inflammation and Tissue Fibrosis

Artunc¹,

Läng

2014

Nephron Physiol

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Effects of mineralocorticoids are not restricted to regulation of epithelial salt transport, extracellular volume and blood pressure; mineralocorticoids also influence a wide variety of seemingly unrelated functions such as inflammation and fibrosis. The present brief review addresses the role of mineralocorticoids in the orchestration of these latter processes. Mineralocorticoids foster inflammation as well as vascular, cardiac, renal and peritoneal fibrosis. Mechanisms involved in mineralocorticoid-sensitive inflammation and fibrosis include the serum- and glucocorticoid-inducible kinase 1 (SGK1), which is genomically upregulated by mineralocorticoids and transforming growth factor β (TGF-β), and stimulated by mineralocorticoid-sensitive phosphatidylinositide 3-kinase. SGK1 upregulates the inflammatory transcription factor nuclear factor-κB, which in turn stimulates the expression of diverse inflammatory mediators including connective tissue growth factor. Moreover, SGK1 inhibits the degradation of the TGF-β-dependent transcription factors Smad2/3. Mineralocorticoids foster the development of T_H17 cells, which is compromised following SGK1 deletion. Excessive SGK1 expression is observed in a wide variety of fibrosing diseases including lung fibrosis, diabetic nephropathy, glomerulonephritis, obstructive kidney disease, experimental nephrotic syndrome, obstructive nephropathy, liver cirrhosis, fibrosing pancreatitis, peritoneal fibrosis, Crohn's disease and celiac disease. The untoward inflammatory and fibrosing effects of mineralocorticoids could be blunted or even reversed by mineralocorticoid receptor blockers, which may thus be considered in the treatment of inflammatory and/or fibrosing disease.

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“…In kidney fibroblasts, physiological levels of aldosterone (10 –9 to 10 –8 m ) can enhance the production of transforming growth factor (TGF)-β 1 , plasminogen activator inhibitor (PAI)-1 and connective tissue growth factor [5,6] and increase mRNA levels of collagen and 3 H-proline incorporation [7]. These findings suggest that aldosterone may regulate matrix production by fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

Aldosterone Induces Kidney Fibroblast Proliferation via Activation of Growth Factor Receptors and PI3K/MAPK Signalling

Huang¹,

Nikolic-Paterson²,

Ma³

et al. 2012

Nephron Exp Nephrol

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Background/Aims: The mineralocorticoid hormone, aldosterone, has pro-fibrotic properties which can cause kidney damage. The severity of kidney interstitial fibrosis is dependent on the accumulation of fibroblasts, which result largely from local proliferation; however, it is unknown whether aldosterone stimulates kidney fibroblast proliferation. Therefore, we examined the effects of aldosterone on the proliferation of cultured kidney fibroblasts. Methods: Uptake of ³H-thymidine and cell number quantitation were used to determine the proliferative effects of aldosterone on a rat kidney fibroblast cell line (NRK49F cells) and interstitial fibroblasts extracted from mouse kidneys after unilateral ureter obstruction. The role of different mitogenic signalling pathways in aldosterone-induced proliferation was assessed using specific inhibitors of receptors and kinases. Results: Physiological levels of aldosterone induced a doubling of proliferation of kidney fibroblasts (p < 0.0001), which was inhibited by pre-treatment with the mineralocorticoid receptor antagonist, eplerenone. Aldosterone-induced fibroblast proliferation was dependent upon the kinase activity of growth factor receptors [platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor]. Notably, PDGF ligands were not involved in aldosterone-induced PDGFR activation, indicating receptor transactivation. Aldosterone-induced fibroblast proliferation also required signalling via PI3K, JNK and ERK pathways, but not via the transforming growth factor-β₁ receptor. Conclusion: Aldosterone ligation of the mineralocorticoid receptor in kidney fibroblasts results in rapid activation of growth factor receptors and induction of PI3K/MAPK signalling, which stimulates proliferation. This suggests that increased levels of aldosterone during disease may promote the severity of kidney fibrosis by inducing fibroblast proliferation.

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Direct Aldosterone Action as a Profibrotic Factor via ROS-Mediated SGK1 in Peritoneal Fibroblasts

Cited by 20 publications

References 71 publications

Rapamycin Attenuates Aldosterone-Induced Tubulointerstitial Inflammation and Fibrosis

Rapamycin Attenuates Aldosterone-Induced Tubulointerstitial Inflammation and Fibrosis

Mineralocorticoid and SGK1-Sensitive Inflammation and Tissue Fibrosis

Aldosterone Induces Kidney Fibroblast Proliferation via Activation of Growth Factor Receptors and PI3K/MAPK Signalling

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