Flutamide regulates renal GR and MR expression in orchiectomized rats depending on salt status

Introduction: Salt restriction is known to protect from development of arterial hypertension. Furthermore, sex differences in blood pressure suggest a modulating role of androgens in the kidney. Little is known about the interaction between androgens and the mineralocorticoid system. This study examined the effect of androgen treatment on renal glucocorticoid (GR) and mineralocorticoid receptor (MR) expression in different states of activation of the renin-angiotensin-aldosterone system.

Methods: Male Wistar rats aged 8-10 weeks were orchiectomized and put on a low-salt (chow 0.03% NaCl + tap water) or high-salt diet (chow 4% NaCl + water 0.09% NaCl) for 5 weeks. They were treated with either placebo, testosterone propionate (T: 1 mg/animal) or 5alpha-dihydrotestosterone (DHT: 1 mg/animal) as daily subcutaneous injection for 16 days (each group n=6). In addition, the animals received the androgen receptor (AR) antagonist flutamide, the MR antagonist spironolactone or placebo, respectively. After sacrifice renal mRNA expression of MR and GR was assessed by realtime PCR.

Results: Sodium loading led to a downregulation of MR mRNA in control animals that received a high-salt diet. This effect could be abolished by spironolactone. DHT caused an upregulation of MR mRNA in salt-depleted animals, but also in animals where AR was blocked. Suppression of MR mRNA in rats on a high-salt diet did not allow any androgen-mediated regulation of the MR. Interestingly, AR blockade by flutamide led to a significant upregulation of MR mRNA in rats on a high-salt diet, whereas downregulation of MR mRNA by flutamide independent of androgen treatment could be seen in salt-depleted rats. Similarly, GR mRNA expression was suppressed in rats on a high-salt diet. This effect was abolished by spironolactone. GR mRNA expression was upregulated by DHT independent of the salt status. After AR blockade this effect was less pronounced. Flutamide itself led to an upregulation of GR mRNA in rats on a high-salt diet, whereas a downregulation of GR mRNA could be seen in salt-depleted rats independent of androgen treatment.

Conclusions: Flutamide regulates both renal MR and GR mRNA expression depending on the salt status of the diet, but irrespective of androgen treatment in orchiectomized rats. Furthermore, androgens increase renal MR and GR mRNA expression. These data reflect a crosstalk of androgens with the mineralocorticoid system in the kidney and a possible AR-independent effect of flutamide.