ALDOSTERONE AND DEXAMETHASONE STIMULATE CALCINEURIN ACTIVITY THROUGH A TRANSCRIPTION-INDEPENDENT MECHANISM INVOLVING STEROID RECEPTOR-ASSOCIATED HEAT-SHOCK PROTEINS
Ja. Tumlin et al., ALDOSTERONE AND DEXAMETHASONE STIMULATE CALCINEURIN ACTIVITY THROUGH A TRANSCRIPTION-INDEPENDENT MECHANISM INVOLVING STEROID RECEPTOR-ASSOCIATED HEAT-SHOCK PROTEINS, The Journal of clinical investigation, 99(6), 1997, pp. 1217-1223
Heat shock proteins (HSP) are components of the steroid receptor compl
ex and are released into the cell cytosol after hormone binding. We te
sted whether HSPs released from steroid receptors mediate an increase
in calcineurin phosphatase activity by steroid hormones. Aldosterone i
ncreased calcineurin activity in microdissected rat cortical collectin
g ducts (CCD) and connecting tubules, but not in proximal tubules, med
ullary thick ascending limb, or outer medullary collecting ducts. In c
ontrast, 5 mu M dexamethasone increased calcineurin activity in both C
CD and proximal tubules. Aldosterone increased CCD calcineurin activit
y after 30 min and this response was blocked by spironolactone, but no
t by actinomycin D. An antibody recognizing HSP-56 did not change basa
l calcineurin activity, but completely blocked the stimulation of calc
ineurin by aldosterone, Rapamycin, an immunosuppressive drug that stab
ilizes the HSP-steroid receptor complex, also blocked the aldosterone
response, whereas HSP-90 or HSP-70 increased calcineurin activity in p
ermeabilized CCD. In summary, (a) aldosterone increases calcineurin ac
tivity in CCD through a transcription-independent process; (b) maneuve
rs inactivating HSP-56 or slowing HSP disassociation from the receptor
complex blocks stimulation of calcineurin by steroid hormones; (c) HS
P-90 and HSP-70 increase CCD calcineurin activity in the absence of st
eroid hormone. We conclude that HSPs released from transformed steroid
receptors can stimulate calcineurin activity through a transcription-
independent pathway.