Mechanisms of inactivation of the action of aldosterone on collecting duct by TGF-beta.
The purpose of these experiments was to investigate the mechanisms whereby transforming growth factor-beta (TGF-beta) antagonizes the action of adrenocorticoid hormones on Na(+) transport by the rat inner medullary collecting duct in primary culture. Steroid hormones 1) increased Na(+) transport by three- to fourfold, 2) increased the maximum capacity of the Na(+)-K(+) pump by 30-50%, 3) increased the steady-state levels of the alpha(1)-subunit of the Na(+)-K(+)-ATPase by approximately 30%, and 4) increased the steady-state levels of the alpha-subunit of the rat epithelial Na(+) channel (alpha-rENaC) by nearly fourfold. TGF-beta blocked the effects of steroids on the increase in Na(+) transport and the stimulation of the Na(+)-K(+)-ATPase and pump capacity. However, there was no effect of TGF-beta on the steroid-induced increase in mRNA levels of alpha-rENaC. The effects of TGF-beta were not secondary to the decrease in Na(+) transport per se, inasmuch as benzamil inhibited the increase in Na(+) transport but did not block the increase in pump capacity or Na(+)-K(+)-ATPase mRNA. The results indicate that TGF-beta does not inactivate the steroid receptor or its translocation to the nucleus. Rather, they indicate complex pathways involving interruption of the enhancement of pump activity and activation/inactivation of pathways distal to the steroid-induced increase in the transcription of alpha-rENaC.
Husted
R F
RF
Department of Internal Medicine, University of Iowa, and Department of Veterans Affairs Medical Center, Iowa City, Iowa 52242, USA.
Sigmund
R D
RD
Stokes
J B
JB
D000450:Aldosterone / Q000494:pharmacology*; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004347:Drug Interactions; D053503:Epithelial Sodium Channels; D005938:Glucocorticoids / Q000494:pharmacology; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000187:drug effects*; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D008901:Mineralocorticoids / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000037:antagonists & inhibitors; D015222:Sodium Channels / Q000235:genetics; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D053503:Epithelial Sodium Channels; D005938:Glucocorticoids; D000451:Mineralocorticoid Receptor Antagonists; D008901:Mineralocorticoids; D012333:RNA, Messenger; D015222:Sodium Channels; D016212:Transforming Growth Factor beta; C013407:benzamil; D000450:Aldosterone; D000584:Amiloride; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase