Blood glucocorticoid levels are regulated by the hypothalamo-pituitary-adrenal/interrenal
axis (HPA axis in mammals, HPI axis in amphibians), and negative feedback by glucocorticoid
signaling is a key player in that regulation. Glucocorticoid and mineralocorticoid
receptors (GR and MR) mediate negative feedback in mam -mals, but little is known
about nuclear receptor-mediated feedback in amphibians. Because amphibians have only
one corticosteroidogenic cell type responsible for glucocorticoid and mineralocorticoid
production, we hypothesized that GR knockout (GRKO) tadpoles have elevated levels
of glucocorticoids and mineralocorticoids as well as axis components regulating their
production. We also examined the response to stress and potential for increased aldosterone
signaling in GRKO tadpoles. We found that GRKO tadpoles have severe hyperactivity
of the HPI axis, namely high mRNA expression levels of pomc, cyp17a1, cyp21a2, cyp11b2,
and star, and high tissue content of corticosterone, aldosterone, 17-hydroxyprogesterone,
21-deoxycortisol, and progesterone. Such aberrant HPI activity was accompanied by
reduced survival after acute temperature shock and shaking stress. Like mammalian
models of HPA hyperactivity, GRKO tadpoles have high MR mRNA expression levels in
brain, kidney, heart, and skin and high levels of the inflammatory cytokine tnf-alpha
and the profibrotic factor tgf-beta in kidneys. This study showed GR is critical for
negative feedback to the amphibian HPI axis and for survival from acute stressors.
This study also showed GRKO tadpoles exhibit altered expression/overproduction of
regulators of salt-water homeostasis and associated biomarkers of kidney disease.
