Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat

Whaley‐Connell, Adam; Habibi, Javad; Wei, Yongzhong; Gutweiler, Alex; Jellison, Jessica; Wiedmeyer, Charles E.; Ferrario, Carlos M.; Sowers, James R.

doi:10.1152/ajprenal.90646.2008

Cited by 43 publications

(53 citation statements)

References 45 publications

(115 reference statements)

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“…40 In transgenic (mRen2)27 (Ren2) rats, which have elevated serum aldosterone levels and increased tissue aldosterone activity, SPL reduces albuminuria and reverts the loss of podocyte-specific proteins and podocyte foot process effacement. 41 These experiments support the hypothesis that MR antagonist has renal protective effect by reducing proteinuria through the restoration of podocyte integrity.…”

Section: Physiological Implicationsupporting

confidence: 66%

Mineralocorticoid Receptor Antagonist for Renal Protection

King-Wing

Szeto

2012

Renal Failure

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The renin-angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular and renal diseases. In chronic kidney disease (CKD), blockade of RAS by angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) has been shown to reduce proteinuria and retard the progression of renal function deterioration. However, aldosterone, another key hormone of the RAS, is not directly targeted by ACEI or ARB. Hyperaldosteronism, apart from promoting sodium and fluid retention, causes inflammation and fibrosis in the heart and kidney. Studies have shown that although plasma aldosterone level shows an initial decrease following ACEI or ARB treatment, it returns to pretreatment level or even increases paradoxically after prolonged treatment. This "aldosterone breakthrough" forms the basis of adding mineralocorticoid receptor (MR) antagonist on top of ACEI or ARB for renal protection. New insights into the pathophysiological role of aldosterone in CKD further expands its potential indications, and there was a growing body of evidence in the past 10 years, which showed a substantial antiproteinuric effect and possibly a considerable renoprotective effect of MR antagonist. Since aldosterone does not act on the efferent glomerular arteriole and has no effect on intraglomerular hemodynamics, the very fact that MR antagonist ameliorates proteinuria sheds light on the physiology of glomerular permeability barrier. This review summarizes the data regarding the theoretical benefit as well as clinical use of MR antagonist in renal diseases.

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Section: Physiological Implicationsupporting

confidence: 66%

Mineralocorticoid Receptor Antagonist for Renal Protection

King-Wing

Szeto

2012

Renal Failure

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“…1,024 × 1,024 pixel images were captured with LSM imaging system under the same microscope and computer settings for all animals of four groups in each experiment. The signal intensities were measured and analyzed in the equal regions with MetaView as previously described [20,21,22,23,24]. …”

Section: Methodsmentioning

confidence: 99%

Nebivolol Reduces Proteinuria and Renal NADPH Oxidase-Generated Reactive Oxygen Species in the Transgenic Ren2 Rat

Whaley‐Connell

Habibi²,

Johnson³

et al. 2009

Am J Nephrol

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Background/Aims: Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system activation are crucial in the pathogenesis of hypertension, cardiovascular and renal disease. NADPH oxidase-mediated increases in reactive oxygen species (ROS) are an important mediator for RAAS-induced cardiovascular and renal injury. Increased levels of ROS can diminish the bioactivity of nitric oxide (NO), a critical modulator of RAAS effects on the kidney. Thereby, we hypothesized that in vivo nebivolol therapy in a rodent model of activated RAAS would attenuate glomerular damage and proteinuria through its actions to reduce NADPH oxidase activity/ROS and increase bioavailable NO. Methods: We utilized the transgenic Ren2 rat which displays heightened tissue RAAS, hypertension, and proteinuria. Ren2 rats (6–9 weeks of age) and age-matched Sprague-Dawley littermates were treated with nebivolol 10 mg/kg/day (osmotic mini-pump) for 21 days. Results: Ren2 rats exhibited increases in systolic blood pressure, proteinuria, kidney cortical tissue total NADPH oxidase activity and subunits (Rac1, p67^phox, and p47^phox), ROS and 3-nitrotyrosine, as well as reductions in podocyte protein markers; each of these parameters improved with nebivolol treatment along with increases in renal endothelial NO synthase expression. Conclusions: Our data suggest that nebivolol improves proteinuria through reductions in renal RAAS-mediated increases in NADPH oxidase/ROS and increases in bioavailable NO.

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“…CTRP1 may be renoprotective in patients with activated MR signaling in target tissue and chronic kidney disease (42). In the transgenic Ren2 rat, podocyte foot process effacement is normalized by treatment with spironolactone and is accompanied by a reduction in albuminuria as well as attenuated NADPH oxidase activity (43). In uninephrectomized rats continuously infused with Ald proteinuria, podocyte damage and SgK1 upregulation are significantly alleviated by tempol, a membranepermeable superoxide dismutase.…”

Section: Aldosteronementioning

confidence: 99%

Obesity-related glomerulopathy and podocyte injury a mini review

Carpi¹

2012

Front Biosci

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Obesity-related glomerulopathy (ORG) is morphologically defined as focal segmental glomerulosclerosis and glomerulomegaly. Podocyte hypertrophy and reduced density are related to proteinuria which in a portion of patients is in the nephrotic range and evolvs towards renal failure. This article reviews the pathogenetic mechanisms of podocyte injury or dysfunction and lists new possible antiproteinuric strategies based on pharmaceutical targeting of the reported pathogenetic mechanisms. The pathogenetic mechnisms discussed include: renin angiotensin system, plasminogen activation inhibitor-1 (PAI-1), lipid metabolism, adiponectin, macrophages and proinflammatory cytokines, oxidative stress. The proposed antiproteinuric strategies include: AT2 receptor blockers; adipokine complement C19 TNF-related protein-1 blocker; selective PAI-1 inhibitor; farnesoid x receptor activation; increase of circulating adiponectin; selective antiinflammatory drugs; more potent antioxidants (Heme oxigenase, NOX4 inhibitors). However, because ORG is a rare disease, the need for a long term pharmaceutical approach in obese proteinuric patients should be carefully evaluated and limited to the cases with progressive loss of renal function.

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Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat

Cited by 43 publications

References 45 publications

Mineralocorticoid Receptor Antagonist for Renal Protection

Mineralocorticoid Receptor Antagonist for Renal Protection

Nebivolol Reduces Proteinuria and Renal NADPH Oxidase-Generated Reactive Oxygen Species in the Transgenic Ren2 Rat

Obesity-related glomerulopathy and podocyte injury a mini review

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