ADRENAL CORTEX AND CORTICOSTEROIDS

1. ADRENAL CORTEX AND CORTICOSTEROIDS

5. Zona glomerulosa • Regulation • Angiotensin II, K+ • Impt enz = P450 aldo • Produces mineralocorticoids • Functions: • Stim’s Na+ reabs’n •  incr’d ECF vol, • Decr’d plasma K+, • Incr’d plasma pH

6. Zona fasciculata • Regulation • ACTH • Impt enz’s • P450c17, P450c11 • Produces • Glucocorticoids • Androgens (androstenedione, DHEA) • Functions • Stress response • Metabolism • Blood pressure • Immune function impacts

7. Zona reticularis • Regulation, enz’s, products same as zona fasciculata • Functions: • Main androgen source in females

8. Corticosteroids • C21 pregnane deriv’s • C19 – androstane deriv’s; C18 – estrane deriv’s • Progesterone, mineralocorticoids, glucocorticoids • Lipophilic • Assoc w/ blood proteins

9. Pregnenolone: produced directly from cholesterol, the precusor molecule for all C-18, C-19 and C-21 steroids  Cortisol:dominant glucocorticoid in humans, synthesized from progesterone in the zona fasciculata of the adrenal cortex, involved in stress adaptation, elevates blood pressure and Na+ uptake, numerous effects on the immune system Aldosterone: the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na+ uptake 

10. Progesterone: a progestin, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteral phase of the menstral cycle, differentiation factor for mammary glands Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone  Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics 

11. Biosynthesis • Cell specific • Cholesterol precursor from cytoplasmic and membr pools • Rate-limiting: cholesterol  mitoch matrix • StAR incorporated into inner mitoch membr • Varied mol’s stim synth de novo • ACTH, LH, hCG •  cAMP    StAR

12. PBR – cholesterol channel • Ubiquitous; act’d by StAR • Assoc’d w/ “mitoch porin” • Cyt P450 enzymes coded by CYP genes • P450 scc catalyzes cholesterol  pregnenolone • Integral to inner mitoch membr • Active site faces matrix

14. Adrenal Cortex Steroidogenic Enzymes • P450c17 catalyzes rxns: • Pregnenolone  17a hydroxypregnenolone or DHEA • Not found in zona glomerulosa • So no glucocorticoids prod’d • DHEA impt to androgen synth • 3bHSD catalyzes rxns: • Pregnenolone  progesterone and • 17a hydroxypregnenolone  17a hydroxyprogesterone

16. P450c21 • Catalyzes rxns: • Pregnenolone  11-deoxycorticosterone (DOC) and • 17a pregnenolone  11-deoxycortisol • Specific to adrenal cortex • DOC only in zona glomerulosa • Only progesterone available • 11-deoxycortisol in other zonae

17. P450 aldo (18 hydroxylase) • Catalyzes 3 rxns: • DOC    aldosterone • In inner mitoch membrane • Introduces C18 aldehyde grp • Expression specific for zona glomerulosa • Induced by • Angiotensin II • Elevated plasma K+

18. P450c11 • Catalyzes rxn: • Deoxycortisol  cortisol (=hydrocortisone) • In inner mitoch membr • Expression specific for zonae fasciculata, reticularis • Induced by ACTH

20. Mineralocorticoids • DOC secr’d by zonae fasciculata, reticularis • ACTH dependent • Potent in vitro • Zona glomerulosa secretes aldosterone • Plasma levels influenced by postural changes • CBG binds 20% • 40% bound to albumin

21. Free aldosterone cleared through kidneys • Inact’n in liver • Reduction, conjugation •  incr’d hydrophilicity, excrn • Stim’s renal Na+ reabs’n, K+ secr’n •  regulation ECF volume, electrolyte composition

22. Renal Na+ Reabsorption • All Na filtered at glomerulus • Approx 1% plasma Na+ excr’d to urine • Reabs’n 65% by proximal tubule • Reabs’n 20-25% by distal tubule • Reabs’n 9% by cortical collecting duct • BUT cortical collecting duct sensitive to hormones • AVP • Aldosterone

26. Aldosterone at Cortical Collecting Duct • Mineralocorticoid receptor • Related to glucocort, progesterone, androgen receptors • Ligand specific hormone-binding domain • Sequence specific DNA-binding domain • Several activities w/ ligand binding:

27. Apical Membr Na+ Channels • Aldosterone receptor occupation  stim’n de novo synth, activity of Na+ channels • Allows Na+ into cell w/ electrochem gradient • Conserves Na+ in body •  Depol’n luminal membr • Dietary Na+ intake 6-8 g/day • Aldosterone stim’d reabs’n max 30 g/day

30. ADH-Regulated Ad Cyclase • Aldosterone receptor occupation  induction expression ad cyclase sensitive to ADH • Impt to aquaporin synth, activation • So concerted reabs’n both water, Na+ • Get isosomotic expansion ECF volume •  Incr’d bp

31. ATPase Activity • Aldosterone receptor occupation  stim’n ATPase • ATP needed to close electrolyte channels in luminal membr • Usually closed, high ATP • When open, K+ out of cells • When aldosterone, ATPase active  decr’d ATP  channel open  K+ out of cell

33. Renin-Angiotensin System • Regulates zona glomerulosa • Angiotensinogen • Glycoprot • Sim to CBG, TBG • Secr’d by liver • Cleaved by proteinase (renin)

34. Renin catalyzes rxn angiotensinogen  angiotensin I • Rate limiting step of pathway • In liver, kidney • Secr’d by cells of juxtaglomerular apparatus • Incr’d renin secr’n w/ • Conditions  decr’d renal blood flow • So w/ decr’d pressure at glomerular afferent arteriole • Angiotensin I cleaved by Angiotensin Converting Enzyme (ACE)  angiotensin II • ACE inhibitors lower bp • Angiotensin II • Biologically active

35. At zona glomerulosa • Angio II receptor heptahelical, G protein-coupled • Receptor occupation w/ angio II  stim’n PLC •  incr’d intracell Ca •  aldosterone synth • Also get act’n PKC, MAP kinase, maybe tyr kinases •  prolif’n zona glomerulosa, vasc sm muscle • Also acts as potent vasoconstrictor by same pathway in vasc smooth muscle

37. Regulation of Renin Secr’n • By feedback mech’s at kidney JGA • Incr’d renin secr’n w/ • Conditions  decr’d renal blood flow • So w/ decr’d pressure at glomerular afferent arteriole • Macula densa = Na+ sensor

40. Tubuloglomerular feedback • Neg feedback between between macula densa NaCl concent and GFR • If NaCl in lumen incr’d, macula densa secr’s adenosine •  afferent arteriole  constriction  decr’d GFR • Short-term adaptation to Na balance • Also  decr’d renin secr’n by JGA • Long-term adaptation to Na balance • If decr’d ECF vol or decr’d NaCl at JGA, get incr’d renin secr’n •  Incr’d angiotensin II, so • Vasc sm muscle constriction • Aldosterone  Na reabs’n  incr’d ECF vol

41. Short-loop feedback • Angiotensin II inhibits renin secr’n from JGA • Long-loop feedback • Aldosterone secr’n regulates Na concent  renin regulation • Plasma renin activity assoc’d w/ sleep rhythms • Impt to bp during sleep cycles

42. Atrial Natriuretic Peptide (Factor) • Opposes action of aldosterone • Decr’s Na+ retention • Decr’s bp • Prod’d by cardiac muscle cells (esp RA) • In response to stretch w/ incr’d venous P • ANP receptor is single-membrane span

43. In kidney, ANP: • Acts at afferent, efferent arterioles •  incr’d bhp  incr’d GFR • Acts at collecting duct • Inhibits Na+ reabs’n •  prod’n autocrine prot • Binds ANP receptor  cGMP  inhib’n Na channel •  diuresis, natriuresis • Inhibits renin secr’n • At adrenal, inhibits aldosterone secr’n • At brain, decr’s salt appetite, ADH secr’n • At vasculature, incr’s permeability of vessels  fluid from IVF  ISF/ICF • Also dilates vessels

45. Glucocorticoids • Cortisol most widely studied • Bound to CBG • Free 4-10% • Liver metab • Reduced, conjugated • Cortisone  cortisol

46. Cortisol • Aid in adaptation to adverse situations • Widespread activities • Receptor widely expressed • Coordinated • Lipophilic • Passes through plasma membranes • Penetrates BBB

47. Glucocorticoid Receptor • Classical action • Homodimer • Glucocort response elements at promoter regions • Act’n or suppression of transcription • Also, transcriptional cross talk • Prot-prot interactions of act’d receptor + other transcr’n factor • So other receptor/transduction pathways impacted • Act’n w/out ligand • Stim’n b2 adr receptor agonists

49. Cortisol Activities • Direct • Ex: Induces enz’s involved in metab pathways • Indirect • Ex: Maintains vasc reactivity to catecholamines • Nongenomic • Ex: Induction PNMT in adrenal medulla