Transcript ADRENAL CORTEX AND CORTICOSTEROIDS

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
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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
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
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
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  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
• 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
• P450 aldo (18 hydroxylase)
– Catalyzes 3 rxns:
• DOC    aldosterone
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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
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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 proteincoupled
– 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 b2 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
–  b 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
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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 b 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 b-LPH, a-MSH, b-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