Effects of mineralocorticoid receptor blockade on glucocorticoid-induced renal injury in adrenalectomized rats

Rafiq, Kazi; Nakano, Daisuke; Ihara, Genei; Hitomi, Hirofumi; Fujisawa, Yoshihide; Ohashi, Naro; Kobori, Hiroyuki; Nagai, Yukiko; Kiyomoto, Hideyasu; Kohno, Masakazu; Nishiyama, Akira

doi:10.1097/hjh.0b013e32834103a9

Cited by 48 publications

(51 citation statements)

References 38 publications

(40 reference statements)

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“…24 In fact, emerging data reveal that aldosterone is not a sole regulator of MR activity. For example, Rafiq et al 25 recently showed that chronic glucocorticoid excess could activate MR and induce the development of renal injury, while Shibata and Fujita 26 identified the signaling crosstalk between MR and small GTPase Rac1 as a novel pathway to facilitate MR signaling. Such a local control system for MR can also be relevant to the pathogenesis of saltsensitive hypertension, and future studies will clarify the detailed mechanism for the intricate regulation of the aldosterone/MR cascade.…”

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confidence: 99%

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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confidence: 99%

Mineralocorticoid Receptor Antagonist for Renal Protection

King-Wing

Szeto

2012

Renal Failure

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“…Some of the injury and renal remodeling may therefore reflect sustained hypertensive barotrauma. Nevertheless, glucocorticoid administration induces glomerulosclerosis, podocyte injury, and albuminuria by MR-dependent, pressure-independent mechanisms (43). We speculate that albuminuria contributes to the morphological changes observed in the kidneys of Hsd11b2 null mice.…”

Section: Discussionmentioning

confidence: 73%

A urine-concentrating defect in 11β-hydroxysteroid dehydrogenase type 2 null mice

Evans

Livingstone

Kenyon

et al. 2012

American Journal of Physiology-Renal Physiology

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In aldosterone target tissues, 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2) is coexpressed with mineralocorticoid receptors (MR) and protects the receptor from activation by glucocorticoids. Null mutations in the encoding gene, HSD11B2, cause apparent mineralocorticoid excess, in which hypertension is thought to reflect volume expansion secondary to sodium retention. Hsd11b2 Ϫ/Ϫ mice are indeed hypertensive, but impaired natriuretic capacity is associated with significant volume contraction, suggestive of a urine concentrating defect. Water turnover and the urine concentrating response to a 24-h water deprivation challenge were therefore assessed in Hsd11b2 Ϫ/Ϫ mice and controls. Hsd11b2Ϫ/Ϫ mice have a severe and progressive polyuric/polydipsic phenotype. In younger mice (ϳ2 mo of age), polyuria was associated with decreased abundance of aqp2 and aqp3 mRNA. The expression of other genes involved in water transport (aqp4, slc14a2, and slc12a2) was not changed. The kidney was structurally normal, and the concentrating response to water deprivation was intact. In older Hsd11b2 Ϫ/Ϫ mice (Ͼ6 mo), polyuria was associated with a severe atrophy of the renal medulla and downregulation of aqp2, aqp3, aqp4, slc14a2, and slc12a2. The concentrating response to water deprivation was impaired, and the natriuretic effect of the loop diuretic bumetanide was lost. In older Hsd11b2 Ϫ/Ϫ mice, the V2 receptor agonist desmopressin did not restore full urine concentrating capacity. We find that Hsd11b2 Ϫ/Ϫ mice develop nephrogenic diabetes insipidus. Gross changes to renal structure are observed, but these were probably secondary to sustained polyuria, rather than of developmental origin. polyuria; polydipsia; aldosterone; corticosterone; aquaporin-2; prenatal programming IN VITRO, ALDOSTERONE AND cortisol have equal affinities for mineralocorticoid receptors (MR) (3). In vivo, however, MR is selectively activated by aldosterone in target tissues such as the distal nephron (aldosterone-sensitive distal nephron; ASDN). This selectivity results from prereceptor metabolism of competing cortisol (corticosterone in rodents), which is an MR ligand, to cortisone (11-dehydrocorticosterone), which is not (16,21).In humans, congenital loss of 11␤ hydroxysteroid dehydrogenase type 2 (11␤HSD2) causes apparent mineralocorticoid excess (AME; OMIM 218030), presenting with hypertension, hypokalemic alkalosis, and a suppressed renin-angiotensinaldosterone system (38, 47). AME reflects activation of MR by glucocorticoids (47): with mineralocorticoid target proteins no longer subject to the homeostatic influence of the renin-angiotensin-aldosterone system, hypertension and electrolyte abnormalities develop secondary to renal salt and water retention. A similar profile is observed when AME is acquired following pharmacological inhibition of 11␤HSD2 (18). In rats, inhibition of 11␤HSD2 stimulates sodium reabsorption in the collecting duct following activation of the epithelial sodium channel (ENaC) (7).To better define the role of 11␤HSD2 in sodium a...

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“…prevented hydrocortisone-induced renal injury in these animals 1 . Another study by Mihailidou et al 2 in Langendrph perfusion system showed that cardiac injury after myocardial infarction was aggravated by physiological dose of cortisol via MR activation without perfusion of aldosterone.…”

Section: Introductionmentioning

confidence: 82%

“…After one week acclimatization, male WKY rats were subjected to right uninephrectomy (UNX) and bilateral adrenalectomy (ADX) by flank incision under sodium pentobarbital anesthesia (50 mg/kg, i.p.) 1 .…”

Section: Methodsmentioning

confidence: 99%

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Possible Contribution of Mineralocorticoid Receptor Activation on Glucocorticoid-Induced Left Ventricular Remodeling in Adrenalectomized Rat

Islam

Sherjee

Mori

et al. 2013

J Bangladesh Soc Physiol

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Background: Chronic glucocorticoid treatment induces the development of renal injury via mineralocorticoid receptor (MR) activation in bilaterally adrenalectomized rats. It has been hypothesized that glucocorticoid contributes to the development of left ventricular (LV) remodeling through MR activation in bilaterally adrenalectomized rats (ADX).Methods: ADX rats were maintained with 1%NaCl in drinking water and randomly treated as follows for 8 weeks: vehicle (n=7), bilateral adrenalectomy (ADX) + hydrocortisone (HYDRO) (5 mg/kg/day, subcutaneous, n=7), and ADX + HYDRO + eplerenone (0.125% in chow; approximately 75 mg/kg/day, n=7). An osmotic minipump was implanted subcutaneously for continuous infusion of HYDRO. Results: As compared with control vehicletreated uninephrectomized rats, ADX+HYDRO treatment for 8 weeks significantly increased systolic blood pressure, LV weight, collagen content and mRNA levels of atrial natriuretic peptide, brain natriuretic peptide, and collagen type 1 and III. These changes were associated with increase in LV thiobarbituric acid reactive substances content, dihydroethidium fluorescence and mRNA levels of NADPH oxidase subunits. Treatment with a selective MR antagonist, eplerenone significantly attenuated HYDRO induced changes in LV parameters. HYDRO-induced increases in mRNA and protein levels of serum and glucocorticoid-regulated kinases 1 were prevented by eplerenone. Conclusion: These data suggest that chronic glucocorticoid treatment induces LV tissue remodeling through MR dependent mechanism in bilateral adrenalectomized rats.

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Effects of mineralocorticoid receptor blockade on glucocorticoid-induced renal injury in adrenalectomized rats

Cited by 48 publications

References 38 publications

Mineralocorticoid Receptor Antagonist for Renal Protection

Mineralocorticoid Receptor Antagonist for Renal Protection

A urine-concentrating defect in 11β-hydroxysteroid dehydrogenase type 2 null mice

Possible Contribution of Mineralocorticoid Receptor Activation on Glucocorticoid-Induced Left Ventricular Remodeling in Adrenalectomized Rat

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