100 24 amineralocorticoids - rutgers · pdf filepage 2 body water and electrolytes •...

Mineralocorticoids

24

Nephron

H2O, ADH, CD

glucose, PCT, Tm

JGA, renin, Ag II,

vasoconstriction,

thirst, aldosterone,

kinins, vasodilation,

Na, ZG, DCT,

ANP, BNP, CNP

endothelin,

adrenomedullin

• Introduction concepts to remember: a) water, glucose, mineral metabolism; b) adrenal in stress and blood pressure

• Renin - angiotensin (RAS) and kallikrein -

kinin (KKS) systems: synthesis, secretion

receptors, mechanism of action, effects

• Mineralocorticoids: aldosterone synthesis, secretion, receptors, mechanism of action, hormonal effects

• Peptide hormones and paracrine factors: ANP, BNP, CNP, ET, adrenomedullin

• Integration: response to hemorrage and to dehydration

• Pathophysiology: RAS & KKS involvement in hypertension and in hyperaldosteronism

Introduction

aldosterone and its

“story lines”

ALDO

renin

Ag II

Body Water and Electrolytes

• Introduction

• RAS & KKS

• Aldosterone

• ANP, ET, adre-nomedullin

• Integration

• Pathologies Distribution of body water and principal electrolytes.

Note that water and electrolytes equilibrate freely between plasma and interstitial fluid, but only water equilibrates between the intracellular and extracellular compartments. The electrochemical gradient for sodium is maintained by the activity of the sodium / potassium ATPase.

The Kidney’s Nephron

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies Schematic representation of renal tubules and their component parts. (Modified from Kriz, W. (1988) A standard nomenclature for structures of the kidney. Am. J. Physiol. 254: F1–F8.)

Countercurrent Mechanism

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies The countercurrent multiplier in the loop of Henle.

Selective permeability of the tubular epithelium and active transport of sodium by the thick ascending limb create osmotic gradients. Tubular to interstitial flow of water concentrates sodium in the descending limb. Sodium movement across the water impermeable ascending limb creates the osmotic gradient in the interstitium. Yellow arrows indicate the direction of flow. Note that active sodium transport in the thick ascending limb creates the gradient in the interstitium and makes the tubular fluid hypoosmotic by the time it emerges from Henle’s loop.

Pituitary and H2O metabolism

AVP released from the PP controls water permeability

in the DCT and collecting ducts of the kidney

AVP

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies


• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies The V1 receptor mediates the pressor actions of AVP/ADH, and the V2 receptor mediates the water conservation effects. The two receptors signal by way of different G-proteins.


• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Principal cells of the collecting duct before (A) and (B) after ADH.

ADH binds to V2 receptors to induce formation of cAMP, which promotes insertion of aquaporin 2 (AQP2) into the luminal membrane making it permeable to water. In the presence of ADH, water can pass through the principal cell from lumen to interstitium driven by the osmotic gradient. Deep in the medulla, urea transporters also are inserted in the luminal membrane in addition to AQP2. Expression of Aquaporins 3 and 4 (Aq 3 & 4) in the basolateral membranes allows osmotic equilibration between intercellular and interstitial water.


• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Aldosterone secreted from the adrenal gland

controls Na absorption in the DCT of the nephron

Adrenal and Na metabolism

ALDO

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Aldosterone secretion is stimulated by the

renin-angiotensin-system and the ANS (S).


ALDO

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies


renin-angiotensin-system and the ANS (S).


ALDO

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Renin - Angiotensin System

• the JGA secretes renin which produces Ag I (10 aa , inactive) from angiotensinogen secreted by the liver

• ACE, found throughout the body, converts Ag I into Ag II (8 aa). Ag II, the most potent vasoconstrictor, also stimulates aldosterone from adrenal ZG. These actions in concert mantain volume and pressure of arterial circulation, and provide major support in times of fluid loss or failing blood pressure

• the major stimulus for renin release is a decrease in perfusion pressure traversing the renal afferent arterioles, which is sensed by the JGA (baroreceptor)

• the 5’-flaking region of the AT1 receptor gene has a glucocorticoid responsive element. The receptor is a classical 7 transmembrane receptor linked to Gq


renin-angiotensin-system (RAS)

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies


• JGA cells act as miniature pressure transducers sensing renal perfusion pressure and corresponding changes in efferent arteriolar perfusion pressure. Reduction in pressure results in the release of renin. Sympathetic ANS regulates renin release in response to standing-up.

• Macula densa cells of DCT are in direct apposition of JGA cells and function as chemoreceptors, monitoring DCT- Na and Cl load

• A number of circulating factors inhibit renin release: Increasing dietary K directly decreases it and Ag II suppresses it independent of alterations in renal blood flow pressure or aldosterone secretion. ANP inhibits renin release. Angiotensinogen (liver) is release constitutively but renin (JGA) is secreted mainly via regulated pathway



• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies




• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies


• Ag II increases aldosterone secretion and constrict vascular smooth muscle, thereby rising blood pressure and reducing blood flow.

• Ag II enhances central sympathetic outflow thus increasing sympathetic NE discharge from nerve terminals. Ag II also releases NE and Epi from the adrenal medulla and ADH

• Ag II may modify ACTH release, has poorly defined CNS functions, cellular growth in its target tissues, and may regulate ovarian and placental function, as for example modifying follicular maturation and atresia



• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies


Angiotensin II derived from the RAS has

multiple effects on its target sites

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies


Different effects of angiotensin II are

elicited by different mechanisms of action

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies


Angiotensin II increases kidney Na reabsorp-

tion, albeit by a different mechanism than Aldo

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Angiotensin II increases sodium reabsorption by stimulating sodium proton exchange in the luminal brush border and sodium bicarbonate cotransport in the basolateral membrane. Hydrogen ions and bicarbonate are regenerated in the cell cytosol from CO2 and water.

RAS / KKS “ying-yang” control of vascular

tone and renal function

Kallikrein - Kinin System

tissuekallikrein

renin

kinase I

kinase II ACE

LMW Kininogen

Kinin

(vasodilator)

Inactiveproducts

Angiotensinogen

Angiotensin I

Angiotensin II(vasoconstrictor)

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies



Kallikrein - Kinin System

• Kinins are involved in regulation of blood pressure and flow, smooth muscle contraction and relaxation, electrolyte and glucose transport, pain, ovulation, sperm mobility and cell proliferation. They play a major role in inflammation by enhancing vascular permeability

• Kinins vasodilator effects counterbalance the vasoconstriction effect of RAS. Tissue kallikrein cleaves kininogen to produce the vasodilator kinin called bradikinin

• HREs have been identified in the 5’-flank-ing region of the kallikrein gene promoter (cAMP, estrogen, P4 and cortisol)

• kallistatin, a kallikrein-BP that inhibits kallikrein activity, is a serin-proteinase inhibitor (serpin) upregulated by E2, P4, GH, T3-T4 and down-regulated in inflammation’s acute phase

• B1 and B2 kinin receptors have only 36% homology. B1 only appears in pathological states (inflammation, trauma) is induced by IL-1, endotoxin and EGF. B2 is upregulated by cAMP and downregulated by salt restric-tion, water deprivation and bradykinin

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies



RAS, KKS and Aldosterone

ALDO

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Aldosterone is a mineralocorticoid secreted by the

adrenal’s zona glomerulosa

aldosterone

Aldosterone Zona Glomerulosa

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

ZG aldosterone

Aldosterone Zona Glomerulosa


adrenal’s zona glomerulosa

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

3BD

I

21BHL

11BHL

18hydrxylase

18dehydrogen...

17alpha

hydroxylase

17alph

adesmolase3BDI

21BHL

11BHL

androstenedione

3BDI

ßhydroxysteroiddehydrogenase

aromatase

aldosterone

cortisol

testosterone

estradiol

mineralocorticoid

pathway

glucocorticoid

pathway

estrogen / androgen

pathway

pregnenolone

progesterone

11-deoxycorti...

corticosterone

18-hydroxycorti...

17 a-hydroxypreg...

17 a-progesterone

11 - deoxycortisol

mevalonic acid AcCoA

SCCEHMG-CoA reductase

VLDL

DHEA

cholesterol pyruvate

(*) metyperonetest

(*)

Biosynthetic Pathway


adrenal’s zona glomerulosa in the adrenal cortex

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Control of biosynthetic path

3BDI

21BHL

11BHL

18hydroxylase

18dehydrogen...

pregnenolone

progesterone

11-deoxycorticosterone

corticosterone

18-hydroxycorticosterone

aldosterone

Ag II

HMG-CoA

reductase

cholesterol AcCoA

SCCE

VLDL

ACTH

LHFSH

Ag II


adrenal’s zona glomerulosa of the adrenal cortex

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Control of biosynthetic path


adrenal’s zona glomerulosa of the adrenal cortex

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Stimulation of aldosterone synthesis by angiotensin II (AII).

AII accelerates the conversion of cholesterol to

pregnenolone and 11- deoxycorticosterone to

aldosterone.

q, = subunits of the guanine nucleotide-

binding protein. PLC = phospholipase C. DAG =

diacylglycerol; IP3 = inositol trisphosphate;

PKC = protein kinase C; CAM kinase II = calcium,

calmodulin-dependent protein kinase II; StAR = steroid acute regulatory

protein.

its main regulatory mechanism is the renin / Ag II system

stimuli for its secretion are high K, low Na, Ag II, and ACTH (disease state)

it increases Na reabsorption and K secretion, volemia, blood pressure, & Na / H ion facilitated diffusion (alkalosis)

its mechanism of action include: 1) increase Na permeability; 2) increase content of Na/K ATPases; 3) increases ATP to Na / K ATPases

aldosterone

Aldosterone’s main physiological effect is the

regulation of Na reabsorption at the DCT

Basal release of Aldosterone

cortisol

renin

aldosterone

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Regulation of Aldosterone

its main regulatory

mechanism is the renin / Ag

II system

stimuli for its secretion are

high K, low Na, Ag II, and

ACTH (disease state)



• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies


its main regulatory

mechanism is the renin / Ag

II system

stimuli for its secretion are

high K, low Na, Ag II, and

ACTH (disease state)



• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Dual negative feedback control of aldosterone secretion. One monitored variable is blood volume, and another is the plasma potassium concentration.


The negative feedback control of renin and

angiotensin secretions.

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Negative feedback control of renin and angiotensin

secretion.

The monitored variable is blood volume detected as

decreases in sodium chloride at the macula

densa, decreased pressure in the afferent arterioles,

and decreased pressure in the carotid sinuses, aortic

arch, and thoracic low pressure receptors.

Coordinated actions of angiotensin restore plasma

volume and abolish the stimuli for renin secretion.

Note that angiotensin II contributes directly and

indirectly to maintenance of blood volume, but its

influence in this regard is inadequate in the absence

of aldosterone.

Effects of Aldosterone

it increases Na reabsorption and K secretion

it increases volemia and

blood pressure

it increases Na / H

facilitated diffusion

(alkalosis)



• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Mechanism of Action

its mechanism of action include:

1) increase Na permeability

2) increase content of Na/K ATPases

3) increases ATP to Na / K ATPases



• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Mechanism of Action







• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Effect of chronic Aldosterone







• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Effects of continuous administration of aldosterone to a normal man. Aldosterone (3–6 mg/day) increased potassium excretion and sodium retention, represented here as a decrease in urinary sodium. The increased retention of sodium, which continued for two weeks, caused fluid retention and hence an increase in body weight. The subject “escaped” from the sodium-retaining effects but continued to excrete increased amounts of potassium for as long as aldosterone was given.

Effect of chronic Aldosterone

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Proposed mechanisms of action of aldosterone in the kidney.

A. Sodium enters principal cells in the cortical collecting ducts through epithelial sodium channels (ENaC), and is extruded into the interstitium by the sodium/potassium ATPase. Potassium exits through ROMK (renal outer medullary K) channels in the luminal surface or through basolateral potassium channels.

B. After a delay of ~30 minutes aldosterone increases expression of the serum glucocorticoid-induced kinase (SGK) 1. SGK1 increases ENaC in luminal membranes by phosphorylating and inactivating the ubiquitin ligase Nedd4-2 that initiates ENaC retrieval. SGK1 also phosphorylates and increases the activity of ROMK channels. MR = mineralocorticoid receptor; HSD II = 11 hydroxysteroid dehydrogenase II.

C. Later effects of aldosterone include increased expression of proteins associated with increased sodium transport.

D. In intercalated cells, aldosterone promotes the secretion of protons by a mechanism that bypasses the nucleus and probably involves an aldosterone receptor on the cell surface (AR) acting through some second messenger. Effects of continuous administration of aldosterone to a normal man. Aldosterone (3–6 mg/day) increased potassium excretion and sodium retention, represented here as a decrease in urinary sodium. The increased retention of sodium, which continued for two weeks, caused fluid retention and hence an increase in body weight. The subject “escaped” from the sodium-retaining effects but continued to excrete increased amounts of potassium for as long as aldosterone was given

ANP,endothelin,adrenomedullin

Aldosterone function is complemented by peptides

acting as hormones and paracrine factors

•Cardiac myocytes produced, both constitutively and in a regulated fashion, 3 natriuretic hormone peptides in response to plasma volume overload or hyperosmo-lality. They unload the vascular tree via a combination of CNS, pituitary, adrenal, vascular, and renal actions.

•ANP/BNP decreased venous return by increasing renal excretion of water and solute, vasorelaxation in certain vascular beds, increased capillary permeability, and decreased cardiac output. ANP is produced in the atrium and BNP is produced in the ventricles.

•CNP produced in endothelium and controls access of blood-born factors not only to interstitium but also to contractile and proliferative elements of the vascular tree (e.g. endothelin, adrenomedullin).

•Endothelin and adrenomdellin are paracrine regulator in multiple tissue systems participating in the main-tenance of circulatory pressure and tissue blood flow

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Atrial Natriuretic Peptide (ANP)

ANP secreted by the heart controls Na excretion at

the level of the kidney’s DCT

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies


• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies Electron microscopic section through rat cardiac atrium showing working cardiac myocytes (x 4,500). G = Storage granules; GC = Golgi complex; My = myofribril; N = nucleus. (From de Bold, A.J. and Bruneau, B.G. (2000) Natriuretic peptides. In Fray, J.C.S., ed. Handbook of Physiology, Section VII, The Endocrine System, Volume 3, Endocrine Regulation of Water and Electrolyte Balance . American Physiological Society/Oxford University Press, 377–409.)

Physiological effects of ANP

ANP has multiple targets beside acting on the kidney

to regulate Na excretion

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies




(atrium) (ventricle) (endothelium)

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies




• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies


(ANP = ANF)

Blood volume or volemia is directly dependent on

plasmatic Na concentration

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies


A decrease in vascular volume is the main negative

feedback regulator of ANF secretion by the heart

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies


increase

venous return

brain

heart

adrenalkidney

RAP

ANP

ALD

cortisolU V

renin

U VNa

selective vasomotion

Starling forces ( HCT)

AVP

salt appetite, water intake

volume and osmo receptors

decrease plasma volume and BP

( - )

peripheral vasculature

ANP interacts with AVP secretion in the control of

blood pressure

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Physiological regulation of ANP

Natriuretic peptides exert multiple effects and are

regulated by multiple factors

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Mechanism of action for ANP

Natriuretic peptides exert their actions by activation

of a membrane receptor linked to Guanylyl Cyclase

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Endothelin (ET)

Endothelin is a paracrine regulator acting as a vaso-

constrictor in multiple tissue systems

vasoconstrictors

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Physiological effects of ET

Endothelin, a vasoconstrictor, participates in the

maintenance of circulatory and tissue blood flow

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Synthesis and Regulation of ET

Endothelin (vasoconstrictor)

Multiple inputs have been shown to affect the

promotor site of the endothelin gene

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Adrenomedullin

Adrenomedullin is a vasodilator paracrine factor

affecting tissue blood pressure and flow

vasodilator

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Effects of Adrenomedullin

Adrenomedullin is a vasodilator paracrine factor

affecting tissue blood pressure and flow

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Synthesis and regulation

Adrenal and gonadal steroids have cholesterol as

their common origin

adrenomedullin

(vasodilator)

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Hormones and hemorrage

With hemorrage, the vascular volume is decreased

without a change in osmolality

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Hormones and dehydration

Dehydration may result from sweating, diarrhea,

vomiting, fever, alcohol, insufficient fluid intake

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Low vs High Salt Ingestion

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies Responses of normal subjects to low or high intake of sodium chloride for five days. Plasma sodium concentrations were maintained within less than 2% by compensating rates of sodium excretion. The small increases or decreases in hematocrit and plasma protein concentrations indicate contraction of the plasma volume in the low sodium group and expansion in the high sodium group. The changes in hormone concentrations are in response to the small changes in osmolality and volume. Plasma renin activity is a measure of renin concentration expressed as ng of angiotensin I formed per ml of plasma in one hour.

plasma Na

hematocrite

ACTH

plasma renin

urine Na

plasma protein

ANF

aldosterone

Hypertension

Both increases in RAS and decreases in KKS

systems are associated with hypertension

• renal kallikrein system and hypertension: findings are consistent with the notion that genetic factors causing a decrease in renal kallikrein activity might contribute to the pathogenesis of hypertension

• renin - angiotensin system and hypertension: increase endogenous Ag II production is accom-panied by hypertension and is reversed by ACE inhibitors. Hypertension has been reported in humans bearing a rare renin - secreting tumor, in patients having a decreased adrenal and renal vascular response to infused Ag II, and in some patients with low renin hypertension having en-hanced adrenal response to Ag II on high Na intake

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Primary Hyperaldosteronism

In a primary endocrine pathology the problem lies in

the endocrine organ in question

removed adrenal adenoma

adenoma

adrenal

adenoma

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Secondary Hyperaldosteronism

In a secondary endocrine pathology the problem lies

someplace else than the endocrine organ in question

Renal artery

stenosis

magnetic resonance

angiography showing the

presence of renal

artery

stenosis (arrow).

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

Secondary Hyperaldosteronism

• Introduction

• RAS & KKS

• Aldosterone


• Integration

• Pathologies

100 24 amineralocorticoids - rutgers · pdf filepage 2 body water and electrolytes •...

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