Renal ischemia-reperfusion injury is prevented by the mineralocorticoid receptor blocker spironolactone

Mejía-Vilet, Juan M.; Ramírez, V Mercy; Cruz, Cristino; Uribe, Norma; Gamba, Gerardo; Bobadilla, Norma A.

doi:10.1152/ajprenal.00077.2007

Cited by 123 publications

(135 citation statements)

References 51 publications

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“…Interestingly, these effects of aldosterone were completely prevented by spironolactone (31). In support to this, we have recently shown that spironolactone completely prevented renal acute injury induced by ischemia-reperfusion by a mechanism that involved preservation of renal plasma flow, reestablishment of urinary NO 2 /NO 3 excretion that was accompanied by increased expression of eNOS and phosphorylation at its residue S1177, as well as by a reduction of lipoperoxidation and cell apoptotic death, indicating indeed that aldosterone also participates in hypoperfusion observed in this model (36).…”

Section: Role Of Aldosterone In Csa Nephrotoxicitysupporting

confidence: 67%

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

Bobadilla¹,

Gamba²

2007

American Journal of Physiology-Renal Physiology

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116

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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 Nephrotoxicitysupporting

confidence: 67%

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

Bobadilla¹,

Gamba²

2007

American Journal of Physiology-Renal Physiology

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116

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“…In addition, renal tubular apoptosis has also been shown to play a critical role in the development of this pathologic condition through induction of tubular cell damage (36). Thus, prevention of renal tubular apoptosis by IgGFc through inhibition of caspase-3 activation might also contribute to reduce both the renal tubular damage and the subsequent renal dysfunction in WT mice subjected to renal I/R.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of FcγRI on Primary Sensory Neurons Increases Insulin-Like Growth Factor-I Production, Thereby Reducing Reperfusion-Induced Renal Injury in Mice

Harada¹,

Zhao²,

Kurihara

et al. 2010

The Journal of Immunology

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Biological role(s) of FcγRI on mouse primary sensory neurons are not fully understood. Sensory neuron stimulation increases insulin-like growth factor-I (IGF-I) production, thereby reducing ischemia/reperfusion (I/R)-induced tissue injury in mice. In this study, we examined whether the Fc fragment of IgG (IgGFc) increases IGF-I production through sensory neuron stimulation, thereby reducing I/R-induced renal injury in mice. IgGFc increased the calcitonin-gene–related peptide (CGRP) release and cellular cAMP levels in dorsal root ganglion neurons isolated from wild-type (WT) mice, whereas, native IgG did not. Pretreatment with anti-FcγRI Ab, a protein kinase A inhibitor KT5710, and a phospholipase A2 inhibitor 4-bromophenylacyl bromide inhibited these effects induced by IgGFc. Administration of IgGFc enhanced increases of renal tissue levels of CGRP and IGF-I and reduced I/R-induced renal injury in WT mice. Increases of renal tissue level of caspase-3, renal accumulation of neutorphils, and renal tubular apoptosis were inhibited by administration of IgGFc in WT mice subjected to renal I/R. Pretreatment with anti–IGF-I Ab completely reversed these effects induced by IgGFc in WT mice. Administration of native IgG did not show any effects in WT mice subjected to renal I/R. None of the effects observed in WT mice was seen after IgGFc administration in CGRP-knockout mice and denervated WT mice. These observations suggest that activation of FcγRI by IgGFc may stimulate sensory neurons, thereby promoting IGF-I production, contributing to reduction of the reperfusion-induced renal injury via attenuation of inflammatory responses in mice.

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“…Hence, we cannot exclude the possibility that there was insufficient time for the rats to develop hyperkalemia. In this respect, it is important to note that, in the previously mentioned study, 9 spironolactone also did not cause hyperkalemia. Consequently, additional studies are needed to confirm that BR-4628 will not increase the risk of hyperkalemia.…”

mentioning

confidence: 51%

“…5 NOX4 expression is increased in tubular epithelial cells, mesangial cells, and podocytes cultured in highglucose media and kidney tissue from different rodent models of diabetes. [6][7][8][9][10] The deleterious effects of NOX4 in these contexts are numerous and extend beyond free radical/oxidant-mediated tissue injury. For example, in addition to reducing ROS levels, transient Nox4 knockdown has been shown to reduce Akt/PKB and extracellular signal-regulated kinase-1/2 phosphorylation in cortical homogenates from diabetic mice 8 and inhibit TGFb1-induced renal myofibroblast activation.…”

mentioning

confidence: 99%

Mineralocorticoid Receptor Antagonism in AKI

Juncos

2016

Journal of the American Society of Nephrology

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AKI is a leading cause of morbidity and mortality in hospitalized patients, particularly among the critically ill, and its incidence is increasing. 1,2 This has piqued the interest of renal researchers, leading to a massive surge in our knowledge of its pathogenesis, systemic effects, and clinical course. Consequently, there has been a paradigm shift in our appreciation of AKI. Classically, AKI was assumed to be a renal-specific, self-limited, reversible condition easily supported by dialysis. Conversely, we now recognize it as a systemic entity that modulates the underlying disease process and causes dysfunction of other organs. 3,4 Moreover, survivors of AKI are at increased risk of long-term adverse outcomes, including CKD, ESRD, cardiovascular events, gastrointestinal bleeding, bone fractures, and premature death. 5,6 Hence, identifying effective therapeutic targets in AKI is of paramount importance. In search of effective therapies, we have vastly increased our mechanistic understanding of AKI; however, we have been less successful at translating this knowledge into clinically relevant therapies, perhaps because of its intricate pathophysiology.AKI is often instigated by a drop in renal perfusion to a level that prevents renal cells from producing sufficient ATP to maintain essential processes. This ischemic injury initiates a response that increases generation of reactive oxygen species, cytokines, chemokines, and leukocyte activation and decreases nitric oxide (NO), thus propagating renal injury. Injury of the endothelial cells leads to microvascular dysfunction characterized by diminished vasodilation and enhanced vasoconstriction. 7 This imbalance between vasoconstriction and vasodilation contributes to the persistent hypoperfusion of the outer medullary region, causing extension of renal injury. 8 Consequently, strategies that diminish this imbalance have attracted much interest. Vasodilators that preferentially increase medullary perfusion, such as NO, may be particularly effective. NO is especially appealing because of its antioxidant, anti-inflammatory, and other beneficial effects. Indeed, agents that augment NO activity (e.g., endothelial nitric oxide synthase [eNOS] -expressing surrogate cells, nitrite, and phosphodiesterase 5 inhibitors) protect against ischemia-reperfusion-induced AKI (I/R-AKI). 7 Alternatively, the imbalance can be improved by blocking vasoconstrictors (e.g., angiotensin II and endothelin [ET]). Because aldosterone has vasoconstrictor, profibrotic, and proinflammatory properties, it may also be an attractive target.In this issue of JASN, Barrera-Chimal et al. 8 provide compelling evidence that BR-4628, a third generation mineralocorticoid receptor (MR) antagonist, is highly protective against experimental I/R-AKI. Moreover, Barrera-Chimal et al. 8 uncover a novel mechanism by which it extends its protection; it prevents AKI-induced inactivation of the ET B receptor, thus normalizing generation of NO. The concept that MR antagonists may be effective against AKI is not novel. I...

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Renal ischemia-reperfusion injury is prevented by the mineralocorticoid receptor blocker spironolactone

Cited by 123 publications

References 51 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

Stimulation of FcγRI on Primary Sensory Neurons Increases Insulin-Like Growth Factor-I Production, Thereby Reducing Reperfusion-Induced Renal Injury in Mice

Mineralocorticoid Receptor Antagonism in AKI

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