Renal Physiology II Flashcards
Note that constriction of the efferent arteriole will cause
Back pressure within the glomerulus
In a healthy nephron, any increase in pressure within the glomerulus will increase
GFR
Low resistance and relatively high pressure environment when compared to that of the systemic capillary network
Between afferent and efferent ends of glomerulus
The combination of low resistance, high pressure (50 mmHg), and enormous surface area of the glomerulus enables the filtration of approximately
180 L of plasma per day
Regulated by the same SNS norepinephrine-adrenoreceptor-dependent mechanism of action that occurs in peripheral vascular smooth muscle
Flow within afferent arteriole
Functions via the intricate concerted actions of the SNS, natiuretic peptides, paracrine factors, and the RAAS
Autoregulation of afferent arteriole flow
Via autoregulation, a fairly narrow range of GFR and RBF can be maintained even in the face of markedly changing
MAP
Occurs in response to 1.) pressure-induced distension of both vascular smooth muscle and the vascular endothelium within the afferent arteriole, and 2.) the tubular glomerular feedback system
Autoregulation
Pressure-induced distension of both vascular smooth muscle and the vascular endothelium within the afferent arteriole is essentially just
Stress induced activation of cation channels, depolarization, Ca2+ influx, and contraction
Uses feedback between several components of the nephron and its microvasculature
Tubular-glomerular-feedback (TGF) system
Regulated by the concentrations of Na+ (or NaCl) in the forming urine as it reaches the cortical thick ascending limb (TAL)
TGF System
In this region of the TAL, there is a population of specialized cells collectively known as the
Macula Densa
These macula densa cells are in close approximation with the
Juxtaglomerular (JG) apparatus
Imbedded around the afferent arteriole
JG apparatus
The JG apparatus contains JG cells (modified smooth muscle cells) that secrete
Renin
As GFR is increased to the upper physiologic limits, we see
Lots of H2O and NaCL in the forming urine
This increased urine NaCl load traverses the nephron to the region of the
Macula Densa
At the macula densa, NaCl delivery (a signal for elevated GFR) stimulates the depolarization of
Macula ensa cells
Upon activation, these macular cells secrete many factors including ATP, adenosine, and thromboxane, each of which target and promote
Vasoconstriction of the afferent arteriole
Vasoconstriction of the afferent arteriole lowers glomerular P, which down-modulates
GFR
In the event of exxagerated volume expansion (increased ECF volume), the sensitivity of the TGF mechanism is decreased because the result of increased GFR is a substantial increase in
H2O and Na+ filtration (pressure natriuresis)
There is lots of Na+ in the filtrate, but there is a lot more H2O, thus the lumenal [Na+] is relatively
Low
Under these conditions, what is the consequence of the relatively low lumenal [Na+]?
The TGF mechanism is more or less desensitized
This sustains a higher
Glomerular P
The higher glomerular P causes increaed GFR, and therefore promotes a higher volume of urine excretion in order to promote
Restoration of BP
In summary, the TGF mechanism is an acute regulator of
GFR
By using Na+ in forming urine as a marker of GFR, the TGF system indirectly interprets volume-pressure status using glomerular pressure and filtration and modulates GFR by controlling
Afferent smooth muscle tone
What are the most important hormones for regulation of renal function?
The members of the RAS, arginine vasopressin (ADH or vasopressin), atrial natriuretic peptide (ANP), norepinephrine, and aldosterone
The only one of these hormones that does not have a direct role in the control of GFR and RBF (renal blood flow) is
Aldosterone
A key component of renal function, and this begins with the mediation of renal organogenesis in utero
Renin-Angiotensin System (RAS)
Throughout life, the RAS functions via endocrine, paracrine, and autocrine mechanisms to modulate
Renal BP and thus regulate GFR
Renal Na+ reabsorption is also modulated by
An-II
A potent vasoconstrictor
An-II
The relatively inert precursor hormones of An-II are
Angiotensinogen and An-I
All components of the RAS are expressed in the
Kidney
Expressed within proximal tubule cells
Angiotensinogen
Present within the proximal tubule brush border
Angiotensin converting enzyme (ACE)
There is also an extrarenal RAS system. This system still depends upon renin from JG secretionm but the angiotensinogen is produced and secreted by
Hepatocytes
Expressed in renal and cardiac tissues where it converts An-II into angiotensin 1-7
ACE2
angiotensin 1-7 binds to Mas, a G-protein coupled receptor, to stimulate
Vasodilation, block proliferation, and promote bradykinin production
Angiotensin 1-7 has actions which counter those of
An-II
Angiotensinogen is targeted by
Renin
A protein hormone that is produced and secreted by the JG cells
Renin
Renin secretion is regulated by which 5 things?
- ) SNS tone (JG cells have B1 adrenoreceptors)
- ) Distension of afferent arteriolar endothelium (elevated BP)
- ) Signals from macula densa
- ) ANP
- ) Negative feedback by An-II
Renin catalyzes the conversion of angiotensinogen into
An-I
The conversion of angiotensinogen into the An-I is the basis for the
-An indicator of RAS activity
Plasma Renin Activity (PRA) assay
Volume depletion leads to lowered BP. This would cause secretion of Renin with asubsequent increase in
PRA
Volume increase leads to elevated BP and the shut off of the
RAS (decreased PRA)
Catalyzes the conversion of An-I to An-II and also the degredation of bradykinin into inactive peptide fragments
Angiotensin Converting Enzyme (ACE)
Bradykinin functions as a
Vasodilator
This, ACE supports vasoconstriction in which two ways?
- ) Production of An-II
2. ) Degredation of bradykinin
During periods of hypovolemia such that normal perfusion pressure can not be maintained, signals are sent to mobilize the
RAS
An-II induces vasoconstriction of systemic arterioles. This raises
BP
An-II dependent constriction of the efferent arteriole steadies
Glomerular P
With constriction of the efferent arterioles by An-II, renal perfusion is reduced leading to lowered P within the
Peritubular capillaries
This enables increased reabsorption of
Na+ and H2O
An-II binds two members of the seven transmembrane G-protein-coupled receptor family known as
AT1 and AT2
Expressed within the smooth muscle of afferent and predominantly efferent arterioles, renal tubules, and peripheral vasculature
-Predominant AT receptor expressed in humans
AT1
In the event of diminished ECV, An-II binds and activates AT1 within the
Efferent arteriole vascular smooth muscle
This induces efferent vasoconstriction and maintains glomerular pressure in order to sustain optimal ultrafiltration across the
Glomerular capillaries
AT1 is also expressed within renal tubules and cells within the
Adrenal zona glomerulosa
Studies in mice have shown that AT1 activity is coupled to the activation of the transporters NHE3, NKCC, NCC, and ENaC, all of which enable
Na+ reabsorption
The main stimulus for aldosterone production and secretion in the adrenal cortex
An-II
AT1 is regionally expressed within the
Renal tubule epithelium and JG cells
Has the ability to both up and down regulate the RAS
An-II
Known to mediate An-II dependent vasoconstriction in the renal efferent arterioles and An-II stimulated Na+ reabsorption from the tubules
AT1
Represents a multileveled feedback-dependent control mechanism for mediating
GFR and Na+ reabsorption
What are three pharmalogical mechanisms designed to target the RAS
- ) ACE inhibitors (enalapril)
- ) ARBs (losartan)
- ) Renin inhibitors (aliskiren)
Has been localized to lung, renal coronary, myocardial tissues, as well as cardiac fibroblasts in the adult
-prevalent during fetal organogenesis
AT2
Experimental evidence indicates that AT2 mediates
Vasodilation and natriuresis
Within renal vascular smooth muscle, promotes the nitric oxide synthase-mediated production of nitric oxide, activation of guanylyl cyclase, the subsequent generation of cGMP
AT2
The nitric oxide synthase-mediated production of nitric oxide, activation of guanylyl cyclase, and the subsequent generation of cGMP is a signaling motif that promotes
Vasodilation
The activation of AT2 can also induce
Bradykinin secretion (a vasodilator and natriuretic factor)
Therefore, the effectos of an ARB may be multi-tierd by
- ) Direct block of AT1 mediated vasoconstriction and Na+ reabsorption
- ) Promoting AT2 release of bradykinin
- ) Promoting AT2 dependent vasodilation and natriuresis
A renin inhibitor that binds with high specificity to the proteolytic active sites within renin and thus blocks its activity
Aliskiren
If renin and/or ACE is blocked, then we disrupt the production of
An-II
Thus, renin and ACE inhibitors can allevite which effects of An-II
An-II’s vasoconstrictive and antinatriuretic effects
In addition, an ACE inhibitor will prevent the ACE-dependent degradation of
Bradykinin
Renin and ACE inhibitors will also tend to lower levels of which hormone?
Aldosterone
However, there are ACE independent pathways for synthesis of
An-II
-ACE independent pathways account for 40% of intrarenal An-II
Also, when An-Ii production is impaired, we actually lose the short loop feedback inhibition of renin. Thus,
Renin activity (measured as PRA) actually increases
This phenomenon is referred to as the
ACE escape
PREganglionic SNS fibers innervate the
Adventitia of renal arteries, tubules, and JG apparatus
POSTganglionic SNS fibers secrete
Norepinephrine
Targets both the afferent and efferent arterioles
Norepinephrine
Activates post-junctional a1 adrenoreceptors within vascular smooth muscle
Norepinephrine
The resulting vasoconstrictive action induces a collective reduction in
-maintains plasma volume
GFR and renal perfusion
Norepinephrine also stimulates renin secretion from JG cells by binding
B1 adrenoreceptors
Elevated SNS activity can enhance some degree of H2O and Na+ reabsorption from tubules via
a2 adrenoreceptors
Thus the collective pattern of increased SNS activity is the
Production of An-II,m conservation of plasma volume by slowing GFR, and enhancing Na+ and H2O reabsorption
A protein hormone that is secreted by neurons that terminate within the posterior pituitary
Arginine Vasopressin (AVP, aka ADH or vasopressin)
AVP is the neuroendocrine hormone that induces the renal-dependent conservation of plasma volume by stimulating
H2O and Na+ reabsorption
AVP also functions as a
Vasoconstrictor
In response to hypoosmolality, osmoreceptors within the neurons of the organus, vasculosus lamina terminales are
Activated
Activation of these osmoreceptors initiates a signal that causes the nerve termini within the posterior pituitary to secrete
AVP
AVP stimulates vasoconstriction within the renal microcirculation and peripheral arterioles by binding to the
V1a receptor isoform
Within the nephron, AVP binds the V2 receptor isoform where it promotes
H2O reabsorption.
AVP promotes H2O reabsorption by inducing the expression and activation of
Aquaporin protein-2 (AQP2)
Also increases the rate of active Na+ reabsorption from the TAL and DCT via its effects on NKCC (TAL), NCC (DCT), and the tubule epithelial Na+ channel (ENaC) (DCT)
AVP
The third isoform of AVP receptor that is expressed in the anterior pituitary, and activation of this receptor is coupled to the secretion of adrenocorticotropic hormone (ACTH)
V1b
