Aldosterone and Mineralocorticoid Receptor Antagonists Modulate Elastin and Collagen Deposition in Human Skin Thomas F. Mitts, Severa Bunda, Yanting.

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Aldosterone and Mineralocorticoid Receptor Antagonists Modulate Elastin and Collagen Deposition in Human Skin Thomas F. Mitts, Severa Bunda, Yanting Wang, Aleksander Hinek Journal of Investigative Dermatology Volume 130, Issue 10, Pages 2396-2406 (October 2010) DOI: 10.1038/jid.2010.155 Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Aldosterone upregulates elastin gene expression and the net deposition of elastic fibers in an MR-independent manner in cultures of dermal fibroblasts. (a) Representative immunofluorescence and western blotting demonstrate expression of mineralocorticoid receptors (MRs) in cultured fibroblasts of human skin. (b) Results of one-step reverse transcriptase-PCR analysis demonstrate that aldosterone causes a dose-dependent increase in levels of collagen type I and elastin messenger RNA (mRNA) transcripts in normal skin fibroblasts. Blocking MR with spironolactone inhibits the aldosterone-induced collagen type I mRNA expression, but enhances expression of elastin mRNA. (c) Immunohistochemistry and (d) quantitative assay of insoluble elastin confirm that aldosterone induces a dose-dependent increase in deposition of elastin in 7-day-old cultures of normal skin fibroblasts and that the addition of spironolactone further intensified the net deposition of elastic fibers. In each experimental group quadruplicate cultures derived from three normal skin biopsies were analyzed (bar=20μM). Journal of Investigative Dermatology 2010 130, 2396-2406DOI: (10.1038/jid.2010.155) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 The MR-independent action of aldosterone stimulates elastin production in cultured dermal fibroblasts via an exclusive activation of IGF-I receptor and triggering the downstream signaling pathway. (a) Results of the quantitative assay of metabolically labeled insoluble elastin in 7-day-old cultures of normal skin fibroblasts. Elastogenic effects of IGF-I and aldosterone are eliminated by anti-IGF-I receptor antibody (αIGF-IR) and IGF-I receptor kinase inhibitor (PPP). In contrast, inhibitors of glucocorticoid receptor (RU 486), angiotensin II receptor type I (losartan), EGFR (AG1478), or transforming growth factor-β receptor (SB 431542) do not eliminate the aldosterone-induced elastogenesis. (b) Inhibitor of c-Src (PP2) eliminates the elastogenic effect of aldosterone (EEA), but does not interfere with the elastogenic effect of IGF-I. Phosphatidylinositol 3-kinase inhibitor (wortmanin) eliminates the elastogenic response of both stimulators. (c) The EEA enhanced by spironolactone or eplerenone is also detected in 7-day-old cultures of fibroblasts isolated from normal skin, stretch-marked skin, hypertrophic scars, and keloids. Journal of Investigative Dermatology 2010 130, 2396-2406DOI: (10.1038/jid.2010.155) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 MR inhibitors differently modulate collagenogenic and elastogenic effects of aldosterone in cultures of fibroblasts derived from stretch-marked skin and keloids. (a) Representative western blots and results of densitometry detecting tropoelastin and collagen type 1 A1 precursor (normalized for β-actin) in 24-hour-old cultures of fibroblasts from five stretch-marked skin samples and five keloids. Treatment with all indicated compounds induces significant effects on the initial production of both precursor proteins. (b) Representative micrographs (bar=20μM) and results of morphometric analysis of immunofluorescence microscopy detecting elastic and collagen I fibers in 7-day-old cultures of fibroblasts derived from 15 samples of stretch-marked skin and five keloids. Both types of fibroblasts treated with the indicated compounds deposit heightened levels of elastic fibers proportional to the levels of tropoelastin detected in 24-hour-old cultures. Keloid fibroblasts jointly treated with aldosterone and spironolactone reveal a remarkable lack of collagen fibers. Journal of Investigative Dermatology 2010 130, 2396-2406DOI: (10.1038/jid.2010.155) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Elastogenic effects of aldosterone and MR inhibitors observed in organ cultures of dermal explants derived from normal and stretch-marked skin. (a) Micrographs of Movat-pentachrome-stained sections of dermal explants derived from the normal abdominal skin of a 30-year-old woman and from a 34-year-old woman with abdominal stretch marks, cultured for 10 days in the presence of specified reagents. Elastin is black, collagen yellow, cells red, and nuclei dark blue (bar=30μM). Results of quantitative morphometric evaluation of elastic fibers (b) and results of quantitative assay of metabolically labeled insoluble elastin (c) in cultured dermal explants of skin fragments derived from 15 normal subjects and from stretch-marked skin fragments excised from 15 patients. Explants treated with the indicated reagents alone produced more elastin than their untreated counterparts. Cultures jointly treated with aldosterone and mineralocorticoid receptor (MR) inhibitors demonstrate more pronounced elastogenic effects than their counterparts treated with aldosterone or MR inhibitors alone. Journal of Investigative Dermatology 2010 130, 2396-2406DOI: (10.1038/jid.2010.155) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Elastogenic effects of aldosterone and MR inhibitors observed in organ cultures of dermal explants derived from hyperthrophic scars and keloids. (a) Micrographs of Movat-pentachrome-stained sections of dermal explants derived from the abdominal scar of a 29-year-old woman and from the abdominal keloid of a 35-year-old woman, cultured for 10 days demonstrating signs of ECM remodeling appearing in response to treatment with indicated reagents (bar=60μM). Results of quantitative morphometric evaluation of elastic fibers (b) and results of quantitative assay of metabolically labeled insoluble elastin (c) performed on 10-day-old cultures of dermal explants derived from seven patients with abdominal scars and five patients with keloids. Results indicate that cultured explants derived from hypertrophic scars or keloids treated with aldosterone, spironolactone, or eplerenone produce more elastic fibers than control explants. Explants treated with aldosterone combined with mineralocorticoid receptor inhibitors contain even more elastic fibers than those treated with aldosterone alone. Journal of Investigative Dermatology 2010 130, 2396-2406DOI: (10.1038/jid.2010.155) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions