ADRENAL CORTEX AND CORTICOSTEROIDS

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

Zona fasciculata

• Regulation – ACTH

• Impt enz’s – P450c17, P450c11

• Produces – Glucocorticoids – Androgens (androstenedione, DHEA)

• Functions – Stress response– Metabolism – Blood pressure– Immune function impacts

Zona reticularis

• Regulation, enz’s, products same as zona fasciculata

• Functions: – Main androgen source in females

Corticosteroids

• C21 pregnane deriv’s– C19 – androstane deriv’s; C18 – estrane deriv’s– Progesterone, mineralocorticoids,

glucocorticoids– Lipophilic– Assoc w/ blood proteins

Pregnenolone: produced directly from cholesterol, the precusor molecule for all C-18, C-19 and C-21 steroids 

Aldosterone: the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na+ uptake 

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

 

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 

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

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

– 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

Adrenal Cortex Steroidogenic Enzymes

• P450c17 catalyzes rxns:– Pregnenolone 17 hydroxypregnenolone or

DHEA– Not found in zona glomerulosa

• So no glucocorticoids prod’d

– DHEA impt to androgen synth

• 3HSD catalyzes rxns:– Pregnenolone progesterone and– 17 hydroxypregnenolone 17

hydroxyprogesterone

• P450c21 – Catalyzes rxns:

• Pregnenolone 11-deoxycorticosterone (DOC) and• 17pregnenolone 11-deoxycortisol

– Specific to adrenal cortex– DOC only in zona glomerulosa

• Only progesterone available

– 11-deoxycortisol in other zonae

• 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+

• P450c11– Catalyzes rxn:

• Deoxycortisol cortisol (=hydrocortisone)

– In inner mitoch membr– Expression specific for zonae fasciculata,

reticularis– Induced by ACTH

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

• 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

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

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:

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

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

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

Renin-Angiotensin System

• Regulates zona glomerulosa

• Angiotensinogen– Glycoprot

• Sim to CBG, TBG

– Secr’d by liver– Cleaved by proteinase (renin)

• 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

• 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

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

• 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

• 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

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

• 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

Glucocorticoids

• Cortisol most widely studied

• Bound to CBG– Free 4-10%

• Liver metab– Reduced, conjugated– Cortisone cortisol

Cortisol

• Aid in adaptation to adverse situations– Widespread activities

• Receptor widely expressed

– Coordinated

• Lipophilic– Passes through plasma membranes– Penetrates BBB

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 2 adr receptor agonists

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

Stress Response

• First: adrenaline incr’s liver glycogenolysis Free glucose– BUT liver glycogen rapidly depleted

• Largest energy store: triglycerides in adipose tissue– Catecholamines, other hormones activate

lipases free fatty acids + glycerol

• FFA cells oxidation acetyl CoA Kreb’s cycle ATP– Incr’d ATP allosterically inhibits glycolysis enz’s

incr’d plasma glucose

• Glucocorts facilitate lipolysis at adipose– Permissive (Fig 15.17)– Provides FFA for liver: induct’n lipolysis @ adipose

ATP, so incr’d plasma glucose

– Induce liver gluconeogenic enz’s Stim’n liver gluconeogenesis

– Mobilizes aa’s from muscle• Used for gluconeogenesis

Cortisol Regulates Immune, Inflamm Responses

• Suppresses prod’n cytokines– Proinflammatory prot’s

• Suppresses transcr’n COX2 (PG synthetase)– Suppresses PG/leukotriene synth– Also inhibits PLA2 so suppresses PG’s

• Induces lipocortins– Autocrine inhibitors of wbc’s

• Suppresses/causes apoptosis of immune cells

Cortisol Direct CNS Effects

• Overprod’n or exogenous glucocort’s memory impairment

• Hippocampal atrophy may be impt to posttraumatic stress disorder

• Limbic system impact impact on mood– Normal cortisol req’d for normal mood– Linkage to sleep cycles?

• Stimulates appetite

Stress Signals• Emotional (anxiety)• Hypoxia, hypercapnia• Hypoglycemia• Decr’d bp or ECF vol• Infections• Env tempt changes• Ethanol consumption• Long-term normocortisolemia req’d for acute

responsiveness to other stress hormones

Circadian Rhythm

• Environmental cues suprachiasmatic nucleus Paraventricular neurons CRH– Lowest cortisol 6-8 a.m.– Highest cortisol 6-10 p.m.

Glucocorticoid Regulation

• Hypothal CRH ant pit corticotrophs ACTH release– Neg feedback control by cortisol– Pulsatile secr’n

• In other brain areas– Synth endorphins

• Outside CNS– Stim synth PGs (proinflammatory)

• CRH-BP– Secr’d by liver, placenta– CRH sink

• CRH receptors in ant pit– CRH1R suppressed by cortisol

• Impt to neg feedback control

• Expressed in other brain areas where related to stress response

• Impt to parturition initiation

– CRH2R impt to vasodilation

• ACTH– POMC derivative

• Also -LPH, -MSH,-endorphins

– Pulsatile secr’n (CRH)– Secr’n stim’d by AVP– Secr’n inhib’d by glucocorticoids (cortisol)

• ACTH receptor– G-prot coupled heptahelical– Stim’s adrenocortical steroidogenesis