Aldosterone receptor antagonism alleviates proteinuria, but not malignant hypertension, in Cyp1a1-Ren2 transgenic rats

Ortiz, Rudy M.; Graciano, Miguel Luis; Mullins, John J.; Mitchell, Kenneth D.

doi:10.1152/ajprenal.00124.2007

Cited by 30 publications

(47 citation statements)

References 37 publications

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“…14,15 Antagonism of the mineralcorticoid receptor (MR, aldosterone receptor) reduces proteinuria and kidney tubulointerstitial fibrosis, independent of changes in blood pressure. [16][17][18][19] In cell culture, aldosterone can activate the Rho kinase pathway, and the Rho kinase pathway is likely responsible for the profibrotic actions of aldosterone in renal proximal tubular epithelial cells via inducing epithelial-mesenchymal transition and extracellular matrix excretion. 20 MR antagonism improves proximal tubule integrity by targeting mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) signaling and redox status independent of changes in blood pressure.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of local aldosterone by eplerenone reduces renal structural damage in a novel model of chronic cyclosporine A nephrotoxicity

Sun

Rui

et al. 2014

J Renin Angiotensin Aldosterone Syst

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Background and objective:The fact that mineralocorticoid receptor antagonists reduce structural and functional alterations induced by cyclosporine A (CsA) indicates that aldosterone plays a key role in chronic CsA nephrotoxicity. We and other researchers have reported local renal aldosterone synthesis. To investigate local renal aldosterone's role in chronic CsA nephrotoxicity, we evaluated the effect of eplerenone (Epl) on renal structural damage and renal dysfunction in adrenalectomized (ADX) rats, and assessed whether the therapeutic benefit was associated with reduction of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), plasminogen activator inhibitor type 1 (PAI-1) and collagen I (COL-I) expression. Methods: Male Sprague-Dawley rats fed a normal-sodium diet were divided in four groups: sham-ADX, ADX, CsA, or Epl. Rats in the ADX, CsA and Epl groups were adrenalectomized first. Aldosterone, sodium and potassium levels in serum and urine were measured on the second day. Two weeks later, vehicle (sham-ADX and ADX group), CsA (25mg/ kg/d), or CsA and Epl (100 mg/ kg/d) combination was administrated, respectively. After six weeks, urinary protein, creatinine clearance (C cr ), tubulointerstitial fibrosis (TIF), aldosterone level in kidney, and renal aldosterone synthase CYP11B2, COL-I, TGF-β1, CTGF and PAI-1 gene expression levels were determined. Results: On the second day after surgery, adrenalectomized rats showed undetectable aldosterone with natriuresis, hyponatremia, decreased urinary potassium excretion and hyperpotassemia. CsA reduced C cr , induced urinary proteins and up-regulated COL-I, TGF-β1, CTGF and PAI-1 gene expression with a significant development of TIF. Eplerenone administration prevented TIF and COL-I, TGF-β1 and PAI-1 up-regulation but did not improve renal function. Conclusion:Our results suggest local renal aldosterone is an important mediator of renal injury induced by CsA.

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Section: Introductionmentioning

confidence: 99%

Inhibition of local aldosterone by eplerenone reduces renal structural damage in a novel model of chronic cyclosporine A nephrotoxicity

Sun

Rui

et al. 2014

J Renin Angiotensin Aldosterone Syst

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“…Previous work in the Ren2, as well as the Cyp1a1-Ren2, suggests that MR antagonism leads to improvements in glomerular damage and proteinuria without reductions in SBP [7,30]. Recent work from our group and others suggest that at early stages of kidney injury there are urine protein contributions derived from either impairments in megalin-mediated endocytosis or the degradation process in PTCs [31,36].…”

Section: Discussionmentioning

confidence: 99%

“…MR-dependent changes in kidney function are thought to largely occur through non-genomic actions including generation of oxidative stress and impairments in metabolic signaling pathways in models of chronic pressure overload [1,2,5]. In this context, recent data highlight a role for antagonism of the MR in reducing proteinuria and kidney tubulointerstitial fibrosis, independent of changes in blood pressure [1,2,5,6,7]. It has been suggested that these blood pressure-independent anti-fibrotic effects of MR antagonism are mediated, in part, through correction of abnormalities in metabolic signaling pathways [8].…”

Section: Introductionmentioning

confidence: 99%

Mineralocorticoid Receptor-Dependent Proximal Tubule Injury Is Mediated by a Redox-Sensitive mTOR/S6K1 Pathway

Whaley‐Connell¹,

Habibi²,

Nistala³

et al. 2011

Am J Nephrol

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Background/Aims: The mammalian target of rapamycin (mTOR) is a serine kinase that regulates phosphorylation (p) of its target ribosomal S6 kinase (S6K1), whose activation can lead to glomerular and proximal tubular cell (PTC) injury and associated proteinuria. Increased mTOR/S6K1 signaling regulates signaling pathways that target fibrosis through adherens junctions. Recent data indicate aldosterone signaling through the mineralocorticoid receptor (MR) can activate the mTOR pathway. Further, antagonism of the MR has beneficial effects on proteinuria that occur independent of hemodynamics. Methods: Accordingly, hypertensive transgenic TG(mRen2)27 (Ren2) rats, with elevated serum aldosterone and proteinuria, and age-matched Sprague-Dawley rats were treated with either a low dose (1 mg/kg/day) or a conventional dose (30 mg/kg/day) of spironolactone (MR antagonist) or placebo for 3 weeks. Results: Ren2 rats displayed increases in urine levels of the PTC brush border lysosomal enzyme N-acetyl-β-aminoglycosidase (β-NAG) in conjunction with reductions in PTC megalin, the apical membrane adherens protein T-cadherin and basolateral α-(E)-catenin, and fibrosis. In concert with these abnormalities, Ren2 renal cortical tissue also displayed increased Ser2448 (p)/activation of mTOR and Thr389 (p)-S6K1 and increased 3-nitrotyrosine (3-NT) content, a marker for peroxynitrite. Low-dose spironolactone had no effect on blood pressure but decreased proteinuria and β-NAG comparable to a conventional dose of this MR antagonist. Both doses of spironolactone attenuated ultrastructural maladaptive alterations and led to comparable reductions in (p)-mTOR/(p)-S6K1, 3-NT, fibrosis, and increased expression of α-(E)-catenin, T- and N-cadherin. Conclusions: Thereby, MR antagonism improves proximal tubule integrity by targeting mTOR/S6K1 signaling and redox status independent of changes in blood pressure.

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“…Radiotelemeters (PA-C40; DSI, St. Paul, MN) were surgically implanted in the abdominal cavity with the catheter end inserted into the descending aorta and fixed in place with a nylon patch and surgical adhesive (39,40). Animals were allowed 5 days to recover from the surgery before initiation of the study.…”

Section: Methodsmentioning

confidence: 99%

Imatinib ameliorates renal morphological changes in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

Graciano

Mitchell

2012

American Journal of Physiology-Renal Physiology

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Graciano ML, Mitchell KD. Imatinib ameliorates renal morphological changes in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension. Am J Physiol Renal Physiol 302: F60 -F69, 2012. First published October 5, 2011 doi:10.1152/ajprenal.00218.2011.-The present study was performed to assess the effects of the platelet-derived growth factor (PDGF) receptor kinase inhibitor imatinib mesylate on the renal morphological changes occurring during the development of malignant hypertension in transgenic rats with inducible expression of the Ren2 gene [TGR(Cyp1a1Ren2)]. Arterial blood pressure was measured by radiotelemetry in male Cyp1a1-Ren2 rats during control conditions and during dietary administration of indole-3-carbinol (I3C; 0.3%) for 14 days to induce malignant hypertension. Rats induced with I3C (n ϭ 5) had higher mean arterial pressures (178 Ϯ 4 vs. 109 Ϯ 2 mmHg, P Ͻ 0.001) and increased urinary albumin excretion (Ualb; 13 Ϯ 5 vs. 0.6 Ϯ 0.2 mg/day) compared with noninduced rats (n ϭ 5). Chronic administration of imatinib (60 mg·kg Ϫ1 ·day Ϫ1 in drinking water, n ϭ 5) did not alter the magnitude of the hypertension (176 Ϯ 8 mmHg) but prevented the increase in Ualb (1.6 Ϯ 0.3 mg/day). Quantitative analysis of proliferating cell nuclear antigen using immunohistochemistry demonstrated increased proliferating cell number in cortical tubules (38 Ϯ 5 vs. 18 Ϯ 1 cells/mm 2 ) and cortical interstitium (40 Ϯ 7 vs. 13 Ϯ 6 cells/mm 2 ) of hypertensive rat kidneys. Renal cortical fibrosis evaluated by picrosirius red staining showed increased collagen deposition in kidneys of the hypertensive rats (1.6 Ϯ 0.1 vs. 0.4 Ϯ 0.1% of cortical area). Imatinib attenuated the increase in proliferating cell number in cortical tubules and interstitium (22 Ϯ 5 vs. 38 Ϯ 5 and 22 Ϯ 6 vs. 40 Ϯ 7 cells/mm 2 , respectively) and reduced the degree of collagen deposition (0.8 Ϯ 0.2 vs. 1.6 Ϯ 0.1%) in the kidneys of hypertensive rats. These findings demonstrate that the renal pathological changes that occur during the development of malignant hypertension in Cyp1a1-Ren2 rats involve activation of PDGF receptor kinase.kidney; immunohistochemistry; renin-angiotensin system; renal pathology; peptide hormones ANG II-DEPENDENT HYPERTENSION is characterized by increases in intrarenal ANG II levels, renal functional derangements, augmented tubular sodium reabsorptive capability, and development of progressive injury to several organs and tissues, including heart, kidney, and blood vessels (11,12,22,30,35,41,49,56,64,70). In contrast, elevated intrarenal ANG II levels alone in the absence of elevated arterial pressure are not associated with perceptible renal injury. Thus, ANG II-induced renal functional and morphological derangements usually occur in a setting of elevated arterial pressure or associated with other pathophysiological conditions such as diabetes mellitus (22,27,30,48,49,59,60,64,66,70). These findings indicate that elevated intrarenal ANG II levels alone are insufficient to cause derangements in renal hemodyna...

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Aldosterone receptor antagonism alleviates proteinuria, but not malignant hypertension, in Cyp1a1-Ren2 transgenic rats

Cited by 30 publications

References 37 publications

Inhibition of local aldosterone by eplerenone reduces renal structural damage in a novel model of chronic cyclosporine A nephrotoxicity

Inhibition of local aldosterone by eplerenone reduces renal structural damage in a novel model of chronic cyclosporine A nephrotoxicity

Mineralocorticoid Receptor-Dependent Proximal Tubule Injury Is Mediated by a Redox-Sensitive mTOR/S6K1 Pathway

Imatinib ameliorates renal morphological changes in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

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