Peritoneal Mesothelial Cells as a Target of Local Aldosterone Action: Upregulation of Connective Tissue Growth Factor Expression via Serum- and Glucocorticoid-Inducible Protein Kinase 1

Okazaki, Akiko; Mori, Yoshihide; Nakata, Midori; Kimura, Takayasu; Sonomura, Kazuhiro; Sakoda, Chikako; Matsuoka, Eiko; Ishida, Mami; Yamahara, Hideki; Kishimoto, Noriko; Nakagawa, Hiromi; Matsubara, Hiroaki

doi:10.1159/000221063

Cited by 11 publications

(5 citation statements)

References 84 publications

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“…33,34 Spironolactone and ARB effectively ameliorated the peritoneal thickening and D/P Cr in the rat scraped peritoneal fibrosis model. 33 In addition, ARB was reported to suppress the deterioration of peritoneal membrane function in PD patients.…”

Section: Discussionmentioning

confidence: 91%

Long-Term Effects of Spironolactone in Peritoneal Dialysis Patients

Ito

Mizuno

Suzuki

et al. 2014

Journal of the American Society of Nephrology

103

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ESRD treated with dialysis is associated with increased left ventricular hypertrophy, which, in turn, is related to high mortality. Mineralocorticoid receptor antagonists improve survival in patients with chronic heart failure; however, the effects in patients undergoing dialysis remain uncertain. We conducted a multicenter, open-label, prospective, randomized trial with 158 patients receiving angiotensin-converting enzyme inhibitor or angiotensin type 1 receptor antagonist and undergoing peritoneal dialysis with and without (control group) spironolactone for 2 years. As a primary endpoint, rate of change in left ventricular mass index assessed by echocardiography improved significantly at 6 (P=0.03), 18 (P=0.004), and 24 (P=0.01) months in patients taking spironolactone compared with the control group. Rate of change in left ventricular ejection fraction improved significantly at 24 weeks with spironolactone compared with nontreatment (P=0.02). The benefits of spironolactone were clear in patients with reduced residual renal function. As secondary endpoints, renal Kt/V and dialysate-to-plasma creatinine ratio did not differ significantly between groups during the observation period. No serious adverse effects, such as hyperkalemia, occurred. In this trial, spironolactone prevented cardiac hypertrophy and decreases in left ventricular ejection fraction in patients undergoing peritoneal dialysis, without significant adverse effects. Further studies, including those to determine relative effectiveness in women and men and to evaluate additional secondary endpoints, should confirm these data in a larger cohort.

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Section: Discussionmentioning

confidence: 91%

Long-Term Effects of Spironolactone in Peritoneal Dialysis Patients

Ito

Mizuno

Suzuki

et al. 2014

Journal of the American Society of Nephrology

103

View full text Add to dashboard Cite

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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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“…Mineralocorticoids further stimulate cardiac and renal fibrosis [33,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56], as discussed in a further contribution to this special issue [57]. …”

Section: Effects Of Mineralocorticoidsmentioning

confidence: 99%

On the Pleotropic Actions of Mineralocorticoids

Läng

2014

Nephron Physiol

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Classical effects of mineralocorticoids include stimulation of Na⁺ reabsorption and K⁺ secretion in the kidney and other epithelia including colon and several glands. Moreover, mineralocorticoids enhance the excretion of Mg²⁺ and renal tubular H⁺ secretion. The renal salt retention following mineralocorticoid excess leads to extracellular volume expansion and hypertension. The increase of blood pressure following mineralocorticoid excess is, however, not only the result of volume expansion but may result from stiff endothelial cell syndrome impairing the release of vasodilating nitric oxide. Beyond that, mineralocorticoids are involved in the regulation of a wide variety of further functions, including cardiac fibrosis, platelet activation, neuronal function and survival, inflammation as well as vascular and tissue fibrosis and calcification. Those functions are briefly discussed in this short introduction to the special issue. Beyond that, further contributions of this special issue amplify on mineralocorticoid-induced sodium appetite and renal salt retention, the role of mineralocorticoids in the regulation of acid-base balance, the involvement of aldosterone and its receptors in major depression, the mineralocorticoid stimulation of inflammation and tissue fibrosis and the effect of aldosterone on osteoinductive signaling and vascular calcification. Clearly, still much is to be learned about the various ramifications of mineralocorticoid-sensitive physiology and pathophysiology.

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Peritoneal Mesothelial Cells as a Target of Local Aldosterone Action: Upregulation of Connective Tissue Growth Factor Expression via Serum- and Glucocorticoid-Inducible Protein Kinase 1

Cited by 11 publications

References 84 publications

Long-Term Effects of Spironolactone in Peritoneal Dialysis Patients

Long-Term Effects of Spironolactone in Peritoneal Dialysis Patients

Mineralocorticoid and SGK1-Sensitive Inflammation and Tissue Fibrosis

On the Pleotropic Actions of Mineralocorticoids

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