Aldosterone and dexamethasone stimulate calcineurin activity through a transcription-independent mechanism involving steroid receptor-associated heat shock proteins.

Tumlin, James A.; Lea, Janice P.; Swanson, Charlotte; Smith, Catharine L.; Edge, S S; Someren, J S

doi:10.1172/jci119278

Cited by 56 publications

(44 citation statements)

References 30 publications

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“…The mineralocorticoid receptor is a protein complex that includes a steroid-binding protein receptor and heat shock proteins (Hsps) of 56, 70, and 90 kDa. Interestingly, Tumlin et al (67) reported that when steroid hormone bound to its receptor, the release of the Hsps complex is able to activate calcineurin phosphatase activity. Also, it has been demonstrated that calcineurin might regulate Na ϩ -K ϩ -ATPase activity through dephosphorylation of its catalytic subunit (30).…”

Section: Role Of Aldosterone In Csa Nephrotoxicitymentioning

confidence: 99%

New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

Bobadilla¹,

Gamba²

2007

American Journal of Physiology-Renal Physiology

117

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Cyclosporine A (CsA), a calcineurin inhibitor, has improved allograft survival in solid organ transplantation and has been increasingly applied in the management of autoimmune diseases. While marked progress has been made in patient and allograft survival rates, clinical use of CsA is often limited by its nephrotoxic effect, which can be presented as two distinct and well-characterized forms: acute and chronic nephrotoxicity. The acute form is characterized by renal vasoconstriction, induced by an imbalance of vasoactive substances release, which leads to renal dysfunction. This form is reversible. The chronic toxicity, in contrast, is characterized by the vasoconstriction plus the development of structural damage that includes arteriolopathy and tubulointerstitial fibrosis that are often not reversible. The exact mechanisms of these deleterious effects are not fully understood, but major advances have occurred over the last few years. Here we review the current literature regarding the pathogenesis and strategies that have been used to ameliorate renal injury in chronic CsA nephrotoxicity. Recent observations suggest that aldosterone plays a central role in the pathogenesis of CsA nephrotoxicity and that spironolactone could be a useful agent to prevent it. These studies and the use of mineralocorticoid receptor blockade are discussed.

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Section: Role Of Aldosterone In Csa Nephrotoxicitymentioning

confidence: 99%

New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

Bobadilla¹,

Gamba²

2007

American Journal of Physiology-Renal Physiology

117

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“…Tumlin et al, 1997;Cissel and Beaven, 2000). These are yet ill-understood and I will not discuss them in further detail.…”

Section: Inhibition Of Signal Transductionmentioning

confidence: 99%

Cross-talk between glucocorticoid receptor and AP-1

2001

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“…Moreover, several rapid aldosterone-induced changes of the concentration of intracellular second messengers have been described. 6,10,11 Aldosterone is reported to activate protein kinase C (PKC) in distal colon cells and cultured kidney cells and to decrease its activity stimulated by phorbol-12-myristate-13-acetate in rat neonatal cardiomyocytes. [12][13][14] However, there is no clear consensus whether PKC is involved in the nongenomic effects of aldosterone on the vascular tone of coronary arteries in the ischemic hearts.…”

mentioning

confidence: 99%

Aldosterone Nongenomically Worsens Ischemia Via Protein Kinase C-Dependent Pathways in Hypoperfused Canine Hearts

et al. 2005

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Abstract-Rapid nongenomic actions of aldosterone independent of mineralocorticoid receptors (MRs) on vascular tone are divergent. Until now, the rapid nongenomic actions of aldosterone on vascular tone of coronary artery and cardiac function in the in vivo ischemic hearts were not still fully estimated. Furthermore, although aldosterone can modulate protein kinase C (PKC) activity, there is no clear consensus whether PKC is involved in the nongenomic actions of aldosterone on the ischemic hearts. In open chest dogs, the selective infusion of aldosterone into the left anterior descending coronary artery (LAD) reduced coronary blood flow (CBF) in the nonischemic hearts in a dose-dependent manner. Also, in the ischemic state that CBF was decreased to 33% of the baseline, the intracoronary administration of aldosterone (0.1 nmol/L) rapidly decreased CBF (37.4Ϯ3.8 to 19.3Ϯ5.2 mL/100 g/min; PϽ0.05), along with decreases in fractional shortening (FS) (8.4Ϯ0.7 to 5.4Ϯ0.4%; PϽ0.05) and lactate extraction rate (LER) (Ϫ31.7Ϯ2.9 to Ϫ41.4Ϯ3.7%; PϽ0.05). The decrease in CBF was reproduced by the infusion of bovine serum albumin-conjugated aldosterone. Notably, these aldosterone-induced deteriorations of myocardial contractile and metabolic functions were blunted by the co-administration of GF109203X, an inhibitor of PKC, but not spironolactone. In addition, aldosterone activated vascular PKC. These results indicate that aldosterone nongenomically induces vasoconstriction via PKCdependent pathways possibly through membrane receptors, which leads to the worsening of the cardiac contractile and metabolic functions in the ischemic hearts. Elevation of plasma or cardiac aldosterone levels may be deleterious to ischemic heart disease through its nongenomic effects. Key Words: aldosterone Ⅲ ischemia Ⅲ protein kinases A ldosterone modulates cardiovascular function in addition to the crucial role in sodium and potassium homeostasis through binding to the intracellular mineralocorticoid receptors (MRs). 1 These receptor-mediated effects with transcriptional modulation of target genes are termed genomic effects. 2 Recently, another pathway possibly mediated by the specific membrane receptors through which aldosterone acts, ie, nongenomic effects of aldosterone, has been investigated. [2][3][4] Although this nongenomic action of aldosterone was shown in a variety of tissues such as vascular smooth muscle cells or cardiomyocytes, the effects of aldosterone on vascular tone are divergent. 4 -9 Aldosterone increased systemic vascular resistance in humans, as shown in the first report on the nongenomic effects of aldosterone, whereas aldosterone inhibits vasoconstriction in renal afferent arterioles. 7-9 Until now, the rapid nongenomic effects of aldosterone on vascular tone of coronary artery and cardiac functions in vivo under ischemia are not still fully estimated. Moreover, several rapid aldosterone-induced changes of the concentration of intracellular second messengers have been described. 6,10,11 Aldosterone is reported to activate pro...

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Aldosterone and dexamethasone stimulate calcineurin activity through a transcription-independent mechanism involving steroid receptor-associated heat shock proteins.

Cited by 56 publications

References 30 publications

New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

Cross-talk between glucocorticoid receptor and AP-1

Aldosterone Nongenomically Worsens Ischemia Via Protein Kinase C-Dependent Pathways in Hypoperfused Canine Hearts

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