Aldosterone as a renal growth factor

Thomas, Warren; Dooley, Ruth; Harvey, Bill

doi:10.1016/j.steroids.2009.09.008

Cited by 22 publications

(11 citation statements)

References 42 publications

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“…A growing body of evidence indicates that MR plays an important role in CV and renal diseases by promoting fibrosis (Thomas et al, 2010;Young and Rickard, 2012). In randomized clinical trials, the beneficial effects of MRA in heart failure were associated with a reduction of fibrosis surrogate markers (Iraqi et al, 2009).…”

Section: Mineralocorticoid Receptor Activation Leads To Fibrosismentioning

confidence: 99%

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

2015

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Section: Mineralocorticoid Receptor Activation Leads To Fibrosismentioning

confidence: 99%

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

2015

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“…Aldosterone can function as a growth factor in cultured collecting duct epithelial cells [33], a cell line more traditionally associated with classical MR and electrolyte transport. Aldosterone has also been shown to induce proliferation in cultured human mesangial cells [34], an effect inhibited by the MR antagonist eplerenone but not the glucocorticoid receptor antagonist RU-486 [27, 34].…”

Section: Mr In Glomerular Cells: Pathogenic Role Of Aldosterone In Glmentioning

confidence: 99%

Therapeutic targeting of aldosterone: a novel approach to the treatment of glomerular disease

Brem

Gong

2015

Clinical Science

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Numerous studies have established a role for mineralocorticoids in the development of renal fibrosis. Originally, the research focus for mineralocorticoid-induced fibrosis was on the collecting duct, where “classical” mineralocorticoid receptors (MR) involved with electrolyte transport are present. Epithelial cells in this segment can, under selected circumstances, also respond to MR activation by initiating pro-fibrotic pathways. More recently, “non-classical” MR have been described in kidney cells not associated with electrolyte transport including mesangial cells and podocytes within the glomerulus. Activation of MR in these cells appears to lead to glomerular sclerosis. Mechanistically, aldosterone induces excess production of reactive oxygen species (ROS) and oxidative stress in glomerular cells through activation of NADPH oxidase. In mesangial cells, aldosterone also has pro-apoptotic, mitogenic, and pro-fibrogenic effects, all of which potentially promote active remodeling and expansion of the mesangium. While mitochondrial dysfunction seems to mediate the aldosterone-induced mesangial apoptosis, the ROS dependent EGFR transactivation is likely responsible for aldosterone-induced mesangial mitosis and proliferation. In podocytes, mitochondrial dysfunction elicited by oxidative stress is an early event associated with aldosterone-induced podocyte injury. Both the p38MAPK signaling and the redox sensitive glycogen synthase kinase (GSK) 3β pathways are centrally implicated in aldosterone-induced podocyte death. Aldosterone-induced GSK3β over-activity could potentially cause hyperphosphorylation and over-activation of putative GSK3β substrates, including structural components of the mitochondrial permeability transition (MPT) pore, all of which lead to cell injury and death. Clinically, proteinuria significantly decreases when aldosterone inhibitors are included in the treatment of many glomerular diseases further supporting the view that mineralocorticoids are important players in glomerular pathology.

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“…Activation of the RAAS may promote renal-cyst growth by means of its mitogenic effects. 14,15 Although this hypothesis has been supported by studies in animals, 16-18 it has not been fully evaluated in patients with ADPKD. It is unclear whether more aggressive antihypertensive therapy or an increased use of RAAS inhibitors delays progression to ESRD in patients with ADPKD.…”

mentioning

confidence: 99%

Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease

et al. 2014

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BACKGROUND Hypertension is common in autosomal dominant polycystic kidney disease (ADPKD) and is associated with increased total kidney volume, activation of the renin–angiotensin–aldosterone system, and progression of kidney disease. METHODS In this double-blind, placebo-controlled trial, we randomly assigned 558 hypertensive participants with ADPKD (15 to 49 years of age, with an estimated glomerular filtration rate [GFR] >60 ml per minute per 1.73 m2 of body-surface area) to either a standard blood-pressure target (120/70 to 130/80 mm Hg) or a low blood-pressure target (95/60 to 110/75 mm Hg) and to either an angiotensin-converting–enzyme inhibitor (lisinopril) plus an angiotensin-receptor blocker (telmisartan) or lisinopril plus placebo. The primary outcome was the annual percentage change in the total kidney volume. RESULTS The annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P = 0.006), without significant differences between the lisinopril–telmisartan group and the lisinopril–placebo group. The rate of change in estimated GFR was similar in the two medication groups, with a negative slope difference in the short term in the low-blood-pressure group as compared with the standard-blood-pressure group (P<0.001) and a marginally positive slope difference in the long term (P = 0.05). The left-ventricular-mass index decreased more in the low-blood-pressure group than in the standard-blood-pressure group (−1.17 vs. −0.57 g per square meter per year, P<0.001); urinary albumin excretion was reduced by 3.77% with the low-pressure target and increased by 2.43% with the standard target (P<0.001). Dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P = 0.002). CONCLUSIONS In early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume. As compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion.

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Aldosterone as a renal growth factor

Cited by 22 publications

References 42 publications

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

Therapeutic targeting of aldosterone: a novel approach to the treatment of glomerular disease

Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease

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