Direct fibrogenic effects of aldosterone on normotensive kidney: an effect modified by 11β-HSD activity

Brem, Andrew S.; Morris, David J.; Ge, Yan; Dworkin, Lance D.; Tolbert, Evelyn; Gong, Rujun

doi:10.1152/ajprenal.00532.2009

Cited by 28 publications

(32 citation statements)

References 45 publications

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“…Interestingly, many of the studies mentioned above used supra-physiological concentrations of mineralocorticoid coupled with induced injury to achieve these effects. Recently, our laboratory demonstrated that low concentrations of aldosterone (10 nM) can directly induce early fibrotic changes in cultured renal collecting duct cells (CCD) in as little as 48 hours 36 . This response in CCD cells, which contain MR and 11β-HSD-2 is consistent with activation of genomic processes.…”

Section: Recent Advancesmentioning

confidence: 99%

Aldosterone-Induced Fibrosis in the Kidney: Questions and Controversies

Brem

Morris

Gong

2011

American Journal of Kidney Diseases

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Over the years, aldosterone has been a favorite topic of renal physiologists given its role in the maintenance of the body fluids. Investigators are only recently coming to appreciate a second pro-inflammatory and pro-fibrotic role for this hormone. Mineralocorticoids, like aldosterone, trigger a pro-fibrotic process, which in many respects mimics the early phase of wound healing. Depending on the type of cell involved, aldosterone may activate the pro-fibrotic process through classical mineralocorticoid receptors (MR), non-classical membrane associated MR, and/or glucocorticoid receptors. In the kidney, the actions of aldosterone can be attenuated by 11-dehydro metabolites of endogenous glucocorticoids generated by isoforms of the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD-1 and 11β-HSD-2). Thus the renal 11β-HSD isoforms may have two functions; to prevent endogenous glucocorticoids from inappropriately binding to and activating MR and to synthesize agents that limit the actions of aldosterone. While sodium in the diet has been implicated in aggravating aldosterone induced renal fibrotic processes, preliminary findings are consistent with the view that aldosterone alone can initiate the matrix production in renal tissue even in the absence of active sodium transport. Thus, there is a growing body of laboratory and clinical evidence supporting the use of inhibitors of aldosterone action in patients with both glomerular and tubular diseases.

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Section: Recent Advancesmentioning

confidence: 99%

Aldosterone-Induced Fibrosis in the Kidney: Questions and Controversies

Brem

Morris

Gong

2011

American Journal of Kidney Diseases

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“…We previously reported how aldosterone elicits renal pathologic lesions in the absence of systemic hemodynamic disturbance like hypertension [34]. Here, ecdysone treatment for 2 weeks also caused early mild accumulation of extracellular matrix in renal tubulointerstitium, as revealed by Masson trichrome staining (for collagen) and by peroxidase immunohistochemistry staining for fibronectin (Fig.…”

Section: Ecdysone Confers An Mr Dependent Nephropathic Effectmentioning

confidence: 58%

Ecdysone Elicits Chronic Renal Impairment via Mineralocorticoid-Like Pathogenic Activities

Wang

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Ecdysteroids are steroidal insect molting hormones that also exist in herbs. Ecdysteroid-containing adaptogens have been popularly used to improve well-being and by bodybuilders for muscle growth. However, the use of ecdysone in mammals is also associated with kidney growth and enlargement, indications of disturbed kidney homeostasis. The underlying pathogenic mechanism remains to be clarified. Methods: Virtual screening tools were employed to identify compounds that are homologous to ecdysone and to predict putative ecdysone-interacting proteins. The kidney effect of ecdysone was examined in vitro and in vivo and compared with that of aldosterone. Cellular apoptosis was estimated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Cell motility was assessed by scratch-wound cell migration assay. Blood urea nitrogen was measured to evaluate renal function. Western immunblot analysis was employed to determine the expression profile of interested proteins. Results: Computational molecular structure analysis revealed that ecdysone is highly homologous to aldosterone. Moreover, virtual screening based on compound-protein interaction profiles identified the Mineralocorticoid Receptor (MR) to potentially interact with ecdysone. Accordingly, to assess potential biological functions of ecdysone in mammals, ecdysone was applied to mineralocorticoid-sensitive inner medullar collecting duct cells. Ecdysone induced mesenchymal accumulation of extracellular matrix and epithelial dedifferentiation characterized by de novo expression of α-smooth muscle actin. In addition, ecdysone elicited cellular apoptosis and retarded cell motility, akin to the effect of aldosterone. In vivo, daily treatment of mice with ecdysone increased cell apoptosis in the kidney, impaired renal function and elicited early signs of renal fibrogenesis, marked by deposition of collagen and fibronectin in tubulointerstitium, reminiscent of the action of aldosterone. The MR signaling pathway is likely responsible for the cellular and pathobiological effects of ecdysone, as evidenced by strong ecdysone-induced MR nuclear translocation in renal tubular cells both in vitro and in vivo, while blockade of MR by concomitant spironolactone treatment largely abolished the detrimental effects of ecdysone. Conclusion: Our findings suggest that ecdysone induces mineralocorticoid-dependent activities that impair renal function and elicit renal injury.

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“…In I/R+Beni+Aldo groups, mice received a continuous infusion of aldosterone by micro pump at a dose of 8 mg kg À1 per day for 4 days. Previous reports [16][17][18][19] and preliminary experiments indicated that this dose of these drugs does not reduce blood pressure in C57BL/6J mice (Supplementary Tables 1 and 2).…”

Section: I/r and Administration Of Drugsmentioning

confidence: 82%