Characterization of renal aldosterone receptors in genetically hypertensive rats

Horiuchi, Masatsugu; Nishiyama, Hiroaki; Hama, Junkichi; Takenaka, Toshihiko; Kondo, Hirokazu; Kino, Hirofumi; Nagata, Shuzo; Sugimura, Keiichi; Katori, Ryo

doi:10.1152/ajprenal.1993.264.2.f286

Cited by 17 publications

(12 citation statements)

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“…Conversely, adrenalectomized rats with glucocorticoid replacement were protected from renal-ablation-induced proteinuria [32]. Similar findings were observed in stroke-prone spontaneously hypertensive rats (SHR) [33,34], in which renal MR contents as well as plasma aldosterone levels are elevated [35]. Indeed, Ang II excess models, such as Ang II/salt rats and double transgenic rats carrying both human renin and human angiotensinogen genes, develop severe albuminuria and kidney injury, which were abrogated by aldosterone synthase inhibitor FAD286, adrenalectomy or MR antagonists [36,37].…”

Section: Aldosterone and Proteinuriasupporting

confidence: 58%

Activation of the aldosterone/mineralocorticoid receptor system in chronic kidney disease and metabolic syndrome

Nagase

2010

Clin Exp Nephrol

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Recent clinical and experimental studies have shown that aldosterone is a potent inducer of proteinuria and that mineralocorticoid receptor (MR) antagonists confer efficient antiproteinuric effects. We identified glomerular epithelial cells (podocytes) as novel targets of aldosterone; activation of MR injures podocytes possibly via oxidative stress, resulting in disruption of glomerular filtration barrier, proteinuria, and progression of chronic kidney disease. We also demonstrated that SHR/cp, a rat model of metabolic syndrome, was susceptible to podocyte injury and proteinuria. Aldosterone excess caused by adipocyte-derived aldosterone-releasing factors was suggested to underlie the nephropathy. High salt intake augmented MR activation in the kidney and exacerbated the nephropathy. Furthermore, we identified an alternative pathway of MR activation by small GTPase Rac1. RhoGDIalpha knockout mice, a model with Rac1 activation in the kidney, showed albuminuria, podocyte injury, and glomerulosclerosis. Renal injury in the knockout mice was accompanied by enhanced MR signaling in the kidney despite normoaldosteronemia, and was ameliorated by an MR antagonist, eplerenone. Moreover, Rac-specific inhibitor significantly reduced the nephropathy, concomitantly with repression of MR activation. In vitro transfection studies provided direct evidence of Rac1-mediated MR activation. In conclusion, our findings suggest that MR activation plays a pivotal role in the pathogenesis of chronic kidney disease in metabolic syndrome, and that MR may be activated both aldosterone dependently (via aldosterone-releasing factors) and independently (via Rac1). MR antagonists are promising antiproteinuric drugs in metabolic syndrome, although long-term effects on renal outcomes, mortality, and safety need to be established.

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Section: Aldosterone and Proteinuriasupporting

confidence: 58%

Activation of the aldosterone/mineralocorticoid receptor system in chronic kidney disease and metabolic syndrome

Nagase

2010

Clin Exp Nephrol

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“…This sensitivity may be one of the underlying processes in hypertension. Blood pressures of SHRs may also be hyperresponsive to mineralocorticoid and its metabolites (10,13), a trend that is not uniformly confirmed (46). Blood pressure is significantly elevated by aldosterone supplementation in adrenalectomized SHRs (10,37).…”

Section: Discussionmentioning

confidence: 99%

Control of oxidative stress in microcirculation of spontaneously hypertensive rats

DeLano¹,

Balete²,

Schmid‐Schönbein³

2005

American Journal of Physiology-Heart and Circulatory Physiology

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One mechanism for organ damage in individuals with arterial hypertension may be due to oxygen free radical production. This study was designed to localize free radicals in a microvascular network of mature spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. Because glucocorticoids play a role in pressure elevation of SHRs, we investigated their role in microvascular free radical formation. Oxygen radical production in mesentery was detected by tetranitroblue tetrazolium reduction to formazan aided by digital light-absorption measurements. Formazan deposits were observed in the endothelial cells and lumens of all microvessels and in lymphatic endothelia but were fewer in tissue parenchyma. The formazan distribution in younger (14 -16 wk old) WKY rats and SHRs was heterogeneous with low values in capillaries and small arterioles/venules (Ͻ30 m) but enhanced deposits in larger venules. Adrenalectomy served to reduce the formazan density in SHRs to the level of WKY rats, whereas dexamethasone supplementation of the adrenalectomized rats caused elevation in the larger venules of SHRs. In older (40 wk old) SHRs, formazan levels were elevated in all hierarchies of microvessels. After pressure reduction was employed with chronic hydralazine treatment, the formazan deposits were reduced in all locations of the microcirculation in both WKY rats and SHRs. Elevated formazan deposits were also found in lymphatic endothelium. These results suggest that oxygen free radical production is elevated in both high-and lowpressure regions of SHR microcirculation via a process that is controlled by glucocorticoids. Older SHRs have higher formazan levels than younger SHRs in all microvessels. Chronic hydralazine treatment, which serves to reduce arterial blood pressure, attenuates tetranitroblue tetrazolium reduction in WKY rats and SHRs even in venules of the microcirculation, which has no micropressure elevation. Free radical production may be a more global condition in SHRs and may not be limited to arteries and arterioles. mesentery; arteriole; capillary; venule; superoxide; nitroblue tetrazolium; dexamethasone; Wistar-Kyoto; adrenalectomy; hydralazine ELEVATION OF ARTERIAL blood pressure is accompanied by a significant risk factor for cardiovascular complications such as stroke, myocardial infarction, atherosclerosis, or renal failure. But the mechanisms that lead to such vascular complications in hypertension are still uncertain. A number of studies indicate that elevated oxygen free radical production may play a role in experimental models of hypertension (12,23,25,26,29,36,44,47) and in human hypertensive individuals (21, 31). Oxygen free radicals such as superoxide, hydrogen peroxide, hydroxyl radical, or peroxynitrite may cause local vascular damage while at the same time producing the hallmarks of hypertension, i.e., increased vascular tone, reduced fluid shear stress response, and arterial pressure elevation (8,9,19,53).Free radicals in hypertension may be derived from a variety of cells in vivo...

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“…Patients with cardiovascular disease and CKD have markedly elevated plasma Aldo concentration; exogenous infusion of Aldo reversed the renoprotective effects of angiotensinconverting enzyme (ACE) inhibitors in hypertensive remnant kidney rats (17) and stroke-prone, spontaneously hypertensive rats (SHRsp) (38). Furthermore, renal expression of the mineralocorticoid receptor (MR) in SHRsp rats was significantly elevated compared with normotensive Wistar-Kyoto rats (21). Blockade of the MR in the N -nitro-L-arginine methyl ester (L-NAME) rat model protected the kidneys without altering blood pressure (39).…”

mentioning

confidence: 99%

Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation

Huang

Zhang²,

Ding³

et al. 2009

American Journal of Physiology-Renal Physiology

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Huang S, Zhang A, Ding G, Chen R. Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation. Am J Physiol Renal Physiol 296: F1323-F1333, 2009. First published April 1, 2009 doi:10.1152/ajprenal.90428.2008.-Aldosterone (Aldo) stimulates glomerular mesangial cell (MC) proliferation, in part, through an ERK1/2-dependent pathway. In this study, we examined whether Aldo activation of ERK1/2 in MC is mediated through redox-dependent EGF receptor (EGFR) transactivation, as well as the involvement of other signaling mechanisms in Aldo-induced MC proliferation. Aldo increased human MC proliferation, as determined by [3 H]thymidine incorporation and cell counts. This increase in proliferation was blocked by inhibition of the mineralocorticoid receptor (MR). Continuing our observations downstream in the signaling pathway, we examined the ability of Aldo to activate both the Ras/MAPK and the PI3K signaling pathways. Aldo increased Ki-RasA and Ki-RasA:GTP levels, and sequentially phosphorylated c-Raf, MAPK kinase (MEK1/ 2), and ERK1/2. Ki-RasA small interfering RNA (siRNA), the c-Raf inhibitor GW5074, and the MEK1/2 inhibitor PD98059 reduced Aldo-induced cell proliferation by ϳ65%. Aldo also increased phosphorylation of PI3K, Akt, the mammalian target of rapamycin (mTOR), and the 70-kDa ribosomal S6 kinase (p70S6K1). Inhibition of the PI3K pathways by the selective PI3K inhibitor LY 294002, an Akt inhibitor, or the mTOR inhibitor rapamycin reduced cell proliferation by 51%. Combining LY 294002 and PD98059 completely blocked Aldo-induced MC proliferation. Next, we confirmed that Aldo exerts its effect on MAPK and PI3K activation, as well as on cell proliferation, by activating the EGFR. Pretreatment with the EGFR antagonist AG1478 inhibited MC proliferation, as well as the activation of Ras/MAPK and PI3K/Akt, suggesting that Ras/MAPK and PI3K/Akt activation occur downstream of EGFR activation. Finally, we examined the role of reactive oxygen species (ROS) in Aldoinduced transactivation of the EGFR. Aldo-induced ROS were predominantly generated by mitochondria. Pretreatment with the antioxidant N-acetyl-L-cysteine, catalase, SOD, mitochondrial respiratory chain complex I inhibitor rotenone (Rot), NADPH oxidase inhibitor apocynin, and DPI significantly inhibited Aldo-stimulated MC proliferation as well as EGFR transactivation. However, Rot reduced MC proliferation more potently than apocynin and DPI. In conclusion, Aldo stimulated cell proliferation through MR-mediated, redox-sensitive EGFR transactivation, which was dependent on the Ki-RasA/ c-Raf/MEK/ERK and PI3K/Akt/mTOR/p70S6K1 signaling pathways in human MCs. reactive oxygen species; PI3KA GROWING BODY OF EVIDENCE suggests that the mineralocorticoid aldosterone (Aldo), a key regulator of blood pressure and electrolytic balance, contributes to the development and progression of cardiovascular disease and chronic kidney disease (CKD), by reducing vascular compliance, as well as promoting endothelial dysfunction and myocardial and renal hy...

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Characterization of renal aldosterone receptors in genetically hypertensive rats

Cited by 17 publications

References 0 publications

Activation of the aldosterone/mineralocorticoid receptor system in chronic kidney disease and metabolic syndrome

Activation of the aldosterone/mineralocorticoid receptor system in chronic kidney disease and metabolic syndrome

Control of oxidative stress in microcirculation of spontaneously hypertensive rats

Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation

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