adrenal cortex and corticosteroids. zona glomerulosa regulation –angiotensin ii, k+ impt enz =...
Post on 22-Dec-2015
219 views
TRANSCRIPT
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