Possible Underlying Mechanisms Responsible for Aldosterone and Mineralocorticoid Receptor–Dependent Renal Injury

Kiyomoto, Hideyasu; Rafiq, Kazi; Mostofa, M; Nishiyama, Akira

doi:10.1254/jphs.08r02cr

Cited by 55 publications

(45 citation statements)

References 51 publications

(66 reference statements)

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“…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][4][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.…”

mentioning

confidence: 99%

Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

Zhu

Huang

Yuan

et al. 2011

The American Journal of Pathology

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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mentioning

confidence: 99%

Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

Zhu

Huang

Yuan

et al. 2011

The American Journal of Pathology

107

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“…A diabetic rat model revealed that the MR antagonist eplerenone in combination with the ACE inhibitor, enalapril enhanced glomerular filtration and suppressed glomerulosclerosis with a concurrent reduction in TGF-1, Collagen type-IV and plasminogen activator factor-1 expression [24]. Aldosterone also stimulates NADPH oxidase-dependent production of reactive oxygen species in renal cells that accelerates fibrosis that can be attenuated using eplerenone [25] . The NF B transcriptional pathway is also activated in response to aldosterone in renal principal collecting duct cells however this was mediated by SGK activity rather than the stimulation of MAP kinases.…”

Section: Aldosterone-induced Signalling and Nephropathymentioning

confidence: 99%

Aldosterone as a renal growth factor

2010

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“…While these studies have focused on cardiomycytes and vascular smooth muscle cells, the recent finding that Rac1 GTPase can modify mineralocorticoid receptor function (25) in association with podocyte damage and proteinuria in the absence of increased systemic aldosterone levels provides an important link between the cardiac and vascular findings and aldosterone-mediated renal injury, fibrosis, and decreased function (25,26).…”

Section: Mineralocorticoid and Angiotensin II Receptor Interactionsmentioning

confidence: 99%

“…High aldosterone levels are associated with inflammatory markers, including IL-6, IL-1 ␤, monocyte chemo-attractant protein-1, reactive oxygen species, increased type IV collagen production, and alterations of plasminogen activator inhibitor and osteopontin expression (26,(33)(34)(35).…”

Section: The Protective Effects Of Mrbsmentioning

confidence: 99%

Mineralocorticoid Receptor Blockers and Chronic Kidney Disease

Jain

Campbell

Warnock

2009

Clinical Journal of the American Society of Nephrology

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The increasing prevalence of chronic kidney disease (CKD) and the public health initiatives for detection and slowing its progression have placed special emphasis on controlling proteinuria and the renin-angiotensin-aldosterone system (RAAS). In addition to the traditional blockers of angiotensin-converting enzyme and angiotensin receptors, mineralocorticoid receptor blockers (MRBs) have come into focus as anti-proteinuric agents with moderate anti-hypertensive effects. The beneficial effects of MRBs on mortality in patients with cardiac disease have been well described. We review the role of aldosterone in end-organ damage, the rationales for using MRBs as adjuncts to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in treating CKD, and the adverse effects that may occur when these agents are used in combination. Suggestions are included for avoiding serious adverse events in CKD patients treated with MRBs. There is a clearly defined need for prospective outcome studies focused on cardiovascular mortality as well as progression of CKD in patients treated with MRBS and other inhibitors of the RAAS.Clin J Am Soc Nephrol 4: 1685 -1691, 2009 . doi: 10.2215 T here are compelling indications for the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in treating patients with chronic kidney disease (CKD), hypertension, and proteinuria, with the expressed goal of preventing progression to ESRD (1). Proteinuria appears to be an independent predictor of renal and cardiovascular outcomes (2,3). Anti-proteinuric therapy is an important part of treatment for slowing progression of CKD (4,5).Increased aldosterone levels are seen in patients treated with ACEIs and ARBs ("escape" or "breakthrough"), supporting the use of MRBs as adjuncts to ACEIs or ARBs (6 -8). As summarized in two recent meta-analyses (9,10), adding MRBs to ACEIs or ARBs: a) reduces proteinuria; b) hyperkalemia can be clinically significant when the estimated GFR (eGFR) is Ͻ30 ml/min/1.73 m 2 , when other drugs that increase serum potassium are used, and when oral potassium supplements are given; and c) the long-term effects of combined therapy on renal outcomes and mortality need to be defined.Randomized controlled trials demonstrate a beneficial effect of adding MRBs to ACEIs or ARBs on survival in patients with left ventricular dysfunction (11,12). MRBs are now widely used in many patients with less severe heart disease, although the supporting evidence is not as strong as for the severe heart failure studies (13). The beneficial cardiac effects of MRBs have not been demonstrated in patients with eGFR Ͻ60 ml/min/ 1.73 m 2 . Recent work has explored the cellular mechanisms of interactions between mineralocorticoid and angiotensin II, type I (AT-1) receptors. Our purpose is to review this information, provide rationales for using MRBs in combination with other inhibitors of the RAAS, and to better define the potential benefits and risks of combined therapy in CKD patients....

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Possible Underlying Mechanisms Responsible for Aldosterone and Mineralocorticoid Receptor–Dependent Renal Injury

Cited by 55 publications

References 51 publications

Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

Mitochondrial Dysfunction Mediates Aldosterone-Induced Podocyte Damage

Aldosterone as a renal growth factor

Mineralocorticoid Receptor Blockers and Chronic Kidney Disease

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