PubMed · 5806682
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P Verroust. 1969-05-03. [Man without kidneys].. https://pubmed.ncbi.nlm.nih.gov/5806682/
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In vitro studies have demonstrated that cysteine groups present in most of the steroid receptors play an essential role in the steroid binding process as well as in the ability of this superfamily of signaling proteins to function as transcription factors. However, there is poor experimental evidence, if any, which demonstrates that under conditions of oxidative stress the steroid receptors in general, and the mineralocorticoid receptor in particular, are affected in vivo in a similar fashion as has been described for cell-free systems or cells in culture. In the present work we report that when mice are exposed to oxidative stress by treatment with L-buthionine-(S,R)-sulfoximine (L-(S,R)-BSO), a glutathione depleting agent, the aldosterone-dependent mineralocorticoid biological response (measured as sodium retention and potassium elimination) was diminished in a directly proportional manner with respect to the depletion of renal glutathione. Accordingly, the steroid binding capacity of the mineralocorticoid receptor was also abrogated, whereas the receptor protein level remained unchanged. The harmful effects observed in mice after glutathione depletion were efficiently prevented by co-treatment with glutathione monoethyl ester. Similar inhibition in the steroid binding capacity was also generated in vitro by receptor alkylation and receptor oxidation, an effect which was prevented in the presence of reducing agents. Since the glutathione deficit generated in vivo by treatment with L-(S,R)-BSO did not significantly affect other renal proteins which are known to be required for the mineralocorticoid mechanism of action, we suggest that in renal cells a low redox potential exerts drastic and uncompensated inhibition of the receptor-mediated mineralocorticoid biological response. This effect was ascribed to the loss of steroid binding capacity of oxidized receptor, most likely by modification of essential cysteines as supported by experiments where a decreased number of reactive thiols and reduced covalent binding of thiol-reactive ligand were evidenced on immunopurified receptor after in vivo treatment with L-(S,R)-BSO.
The interrelationship between thyroid hormones and aldosterone has been examined in the regulation of rat colonic amiloride-sensitive Na+ transport which translocates Na+ through apical amiloride-sensitive Na+ channels and basolateral Na+, K+-ATPase. Electrogenic Na+ transport was measured in an Ussing chamber by the short-circuit current and identified by Na+ channel blocker amiloride. Na+-pumping activity of the basolateral Na+,K+-ATPase was investigated in nystatin-treated epithelium by measuring the equivalent short-circuit current after addition of mucosal Na+. The abundance of mRNA coding for alpha, beta and gamma subunits of the Na+ channel (rENaC) was estimated using Northern blot analysis. Hyperaldosteronism was induced by a low-salt diet and hypothyroidism by methimazole. The low-Na+ diet induced electrogenic Na+ transport in euthyroid rats but its effect was almost completely inhibited in hypothyroid animals even if the plasma concentration of aldosterone was high enough to stimulate this transport pathway both in euthyroid and hypothyroid rats. A kinetic study of the basolateral Na+,K+-ATPase revealed a decrease of Na+ transport capacity in hypothyroid rats kept on the low-Na+ diet in comparison with euthyroid animals fed the same diet. No significant differences in steady-state levels of alpha, beta and gamma rENaC mRNA were detected between euthyroid and hypothyroid rats. These data suggest that hypothyroidism decreases the efficacy of the basolateral Na+ pump but fails to inhibit it completely even though it inhibits the transepithelial electrogenic Na+ transport in response to aldosterone. We conclude that the permissive effect of thyroid hormones on the induction of electrogenic Na+ transport by aldosterone is localised beyond the transcriptional step of Na+ channel regulation.
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