Inhibition of tissue repair by spironolactone

Role of mineralocorticoids in fibrous tissue formation

Simon H. Slight, Vijay K. Chilakamarri, Samer Nasr, Arvinder K. Dhalla, Felix J.A. Ramires, Yao Sun, Venkataseshu K. Ganjam, Karl Weber

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Mineralocorticoids have been implicated in promoting fibrous tissue formation in various organs. In the present study, we sought to address the potential contribution of mineralocorticoids to fibrous tissue formation using a skin pouch model which has proved valuable for the analysis of inflammatory and wound healing responses. Skin pouches were induced in rats by administration of a phorbol ester, croton oil (0.5 ml of a 1% solution). After 2 weeks, rats were killed and intact pouch tissue collected. Pouch weights of control and aldosterone-treated (0.75 μg/h via osmotic minipump) rats were similar (3.33 ± 0.44 g vs. 3.70 ± 0.28 g respectively). However, pouch weights were reduced by more than 50% in spironolactone-treated (25 mg/day powdered in food) animals (1.62 ± 0.22 g and 1.27 ± 0.23 g respectively in aldosterone and spironolactone alone groups). To ascertain the effects of different treatments on collagen accumulation, hydroxyproline concentration was measured. Compared with controls, hydroxyproline concentration was significantly reduced following spironolactone treatment (17.1 ± 0.08 vs. 7.5 ± 2.0 μg/mg dry wt, respectively, p < 0.01). This response to spironolactone was negated by coadministration of aldosterone (hydroxyproline concentration was 18.6 ± 2.1 μg/mg dry wt). Following bilateral adrenalectomy, spironolactone reduced pouch weight and hydroxyproline concentration, which was not the case for adrenalectomy alone. Two week aldosterone administration in uninephrectomized rats on high salt diet was deemed ineffective in modulating pouch development (pouch wet wts were 3.48 ± 0.4 g vs. 3.00 ± 0.19 g in respectively). Mineralocorticoid receptor expression in pouch tissue was demonstrated by RT/PCR. Furthermore, NADP+-dependent 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity was detected in pouch tissue, together with lower levels of NAD+-dependent 11β-HSD2. Spironolactone (p < 0.05) significantly reduced 11β-HSD1 activity compared with controls. Thus, fibrous tissue possesses requisite components of MC action, and antagonism of mineralocorticoid receptors by spironolactone attenuates its formation. Pouch formation is under the influence of circulating MC and, we would like to propose, is also mediated through corticosteroids generated de novo at the site of tissue repair.

Original languageEnglish (US)
Pages (from-to)47-54
Number of pages8
JournalMolecular and Cellular Biochemistry
Volume189
Issue number1-2
StatePublished - Dec 18 1998
Externally publishedYes

Fingerprint

Mineralocorticoids
Spironolactone
Repair
Tissue
Hydroxyproline
Aldosterone
Rats
11-beta-Hydroxysteroid Dehydrogenases
Mineralocorticoid Receptors
Adrenalectomy
Weights and Measures
Skin
Croton Oil
Phorbol Esters
Nutrition
NADP
NAD
Wound Healing
Adrenal Cortex Hormones
Animals

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Slight, S. H., Chilakamarri, V. K., Nasr, S., Dhalla, A. K., Ramires, F. J. A., Sun, Y., ... Weber, K. (1998). Inhibition of tissue repair by spironolactone: Role of mineralocorticoids in fibrous tissue formation. Molecular and Cellular Biochemistry, 189(1-2), 47-54.

Inhibition of tissue repair by spironolactone : Role of mineralocorticoids in fibrous tissue formation. / Slight, Simon H.; Chilakamarri, Vijay K.; Nasr, Samer; Dhalla, Arvinder K.; Ramires, Felix J.A.; Sun, Yao; Ganjam, Venkataseshu K.; Weber, Karl.

In: Molecular and Cellular Biochemistry, Vol. 189, No. 1-2, 18.12.1998, p. 47-54.

Research output: Contribution to journalArticle

Slight, SH, Chilakamarri, VK, Nasr, S, Dhalla, AK, Ramires, FJA, Sun, Y, Ganjam, VK & Weber, K 1998, 'Inhibition of tissue repair by spironolactone: Role of mineralocorticoids in fibrous tissue formation', Molecular and Cellular Biochemistry, vol. 189, no. 1-2, pp. 47-54.
Slight SH, Chilakamarri VK, Nasr S, Dhalla AK, Ramires FJA, Sun Y et al. Inhibition of tissue repair by spironolactone: Role of mineralocorticoids in fibrous tissue formation. Molecular and Cellular Biochemistry. 1998 Dec 18;189(1-2):47-54.
Slight, Simon H. ; Chilakamarri, Vijay K. ; Nasr, Samer ; Dhalla, Arvinder K. ; Ramires, Felix J.A. ; Sun, Yao ; Ganjam, Venkataseshu K. ; Weber, Karl. / Inhibition of tissue repair by spironolactone : Role of mineralocorticoids in fibrous tissue formation. In: Molecular and Cellular Biochemistry. 1998 ; Vol. 189, No. 1-2. pp. 47-54.
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abstract = "Mineralocorticoids have been implicated in promoting fibrous tissue formation in various organs. In the present study, we sought to address the potential contribution of mineralocorticoids to fibrous tissue formation using a skin pouch model which has proved valuable for the analysis of inflammatory and wound healing responses. Skin pouches were induced in rats by administration of a phorbol ester, croton oil (0.5 ml of a 1{\%} solution). After 2 weeks, rats were killed and intact pouch tissue collected. Pouch weights of control and aldosterone-treated (0.75 μg/h via osmotic minipump) rats were similar (3.33 ± 0.44 g vs. 3.70 ± 0.28 g respectively). However, pouch weights were reduced by more than 50{\%} in spironolactone-treated (25 mg/day powdered in food) animals (1.62 ± 0.22 g and 1.27 ± 0.23 g respectively in aldosterone and spironolactone alone groups). To ascertain the effects of different treatments on collagen accumulation, hydroxyproline concentration was measured. Compared with controls, hydroxyproline concentration was significantly reduced following spironolactone treatment (17.1 ± 0.08 vs. 7.5 ± 2.0 μg/mg dry wt, respectively, p < 0.01). This response to spironolactone was negated by coadministration of aldosterone (hydroxyproline concentration was 18.6 ± 2.1 μg/mg dry wt). Following bilateral adrenalectomy, spironolactone reduced pouch weight and hydroxyproline concentration, which was not the case for adrenalectomy alone. Two week aldosterone administration in uninephrectomized rats on high salt diet was deemed ineffective in modulating pouch development (pouch wet wts were 3.48 ± 0.4 g vs. 3.00 ± 0.19 g in respectively). Mineralocorticoid receptor expression in pouch tissue was demonstrated by RT/PCR. Furthermore, NADP+-dependent 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity was detected in pouch tissue, together with lower levels of NAD+-dependent 11β-HSD2. Spironolactone (p < 0.05) significantly reduced 11β-HSD1 activity compared with controls. Thus, fibrous tissue possesses requisite components of MC action, and antagonism of mineralocorticoid receptors by spironolactone attenuates its formation. Pouch formation is under the influence of circulating MC and, we would like to propose, is also mediated through corticosteroids generated de novo at the site of tissue repair.",
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