renin-angiotensin system | Definition & Facts | index-art.info
The renin–angiotensin system (RAS) or the renin–angiotensin–aldosterone system (RAAS) is a hormone system that regulates blood pressure and fluid balance. Renin is an enzyme that controls aldosterone production. Aldosterone and renin tests help diagnose primary (Conn syndrome) and secondary. Pseudohypoaldosteronism, an aldosterone resistance syndrome due to endocrinopathy, M protein and skin changes (POEMS) syndrome, lead . aldosterone concentrations in relation to elevated plasma renin activity (94).
These mineralocorticoid antagonists may antagonize aldosterone at the levels of mineralocorticoid receptor 54 and frequently, these states are compensated for by elevated concentrations of plasma aldosterone.
Presentation The most common form of isolated hypoaldosteronism is caused by impaired renin release from the kidney. Hyperchloremic metabolic acidosis is seen in approximately half of the patients.
This acidosis is classified as a renal tubular acidosis type IV The acidosis is a consequence of decreased renal ammonia neogenesis, reduced hydrogen ion-secretory capacity in the distal nephron and mild reduction in the proximal tubular threshold for bicarbonate reabsorption. Occasionally, muscle weakness or cardiac arrhythmias are present in some patients. More than a half of the patients have diabetes mellitus Other frequently associated states include autonomic neuropathy, hypotension and various nephropathies such as glomerulonephritis, gouty nephropathy and pyelonephritis Moreover, this syndrome occurs transiently in association with use of non-steroidal anti-inflammatory drugs, cyclosporin A, mitomycin C, cosyntropin and other agents in susceptible individuals Pathophysiology Urinary aldosterone excretion is low under basal conditions and fails to increase after sodium restriction.
Plasma renin activity is also low and does not increase appropriately during sodium restriction, periods of prolonged upright posture, or diuretic administration Interstitial renal disease and damage to the juxtaglomerular apparatus seems the most likely cause for the primary defect in renin generation or release and secondary deficiency of aldosterone.
However, in some patients with this syndrome there is an absent or blunted aldosterone response to angiotensin II 73,74suggesting a coexisting primary defect in aldosterone secretion or it reflects atrophy of the zona glomerulosa caused by chronic renin deficiency. There are various mechanisms to be explained the hyporeninemia. First possible mechanism is the hypervolemia.
Aldosterone Secretion in Hypertension
The expanded extracellular fluid volume due to hypertension may suppress renin. In fact, long-term sodium restriction and diuretic administration increase plasma renin activity in these patients, however, the increments of plasma renin activity are less than those of normal subjects A second possible mechanism is insufficiency of the autonomic nervous system, particularly in patients with diabetic neuropathy.
Impaired adrenergic response to postural change may contribute to insufficient renin release. A third proposed mechanism is secretion of abnormal forms of renin, such as a defect in the conversion of prorenin to renin. Insufficiency of autonomic nervous system may be associated with impaired conversion of prorenin to renin. Indeed, diabetic patients with autonomic neuropathy have elevated plasma levels of prorenin A fourth possibility is prostaglandin deficiency.
Furthermore, the prostaglandin I2 in these patients was unresponsive to the potent stimulators norepinephrine and calcium.
Prostaglandin I2 deficiency may cause hyporeninemic hypoaldosteronism by causing defects in the conversion of prorenin to renin 80 and renin release. Diagnosis The diagnosis of hyporeninemic hypoaldosteronism must be considered in any patient with unexplained hyperkalemia.
Excess potassium intake from food or drugs does not cause sustained hyperkalemia, if renal function is normal. Renal function should be evaluated and drugs that impair renal potassium excretion should be excluded as a cause. A low random plasma renin concentration associated with a normal ratio of aldosterone to plasma renin activity is also useful for the diagnosis 81, Therapy The therapeutic approach should be chosen after taking into consideration the age of the patients and other concurrent disorders.
Only monitoring potassium concentrations is enough for patients with moderate hyperkalemia and without electro-cardiographic changes. Dietary potassium intake should be reduced, if possible. Diuretics are the initial treatment for patients who have disorders associated with sodium retention, such as hypertension and congestive heart failure. Mineralocorticoid replacement with fludrocortisone is reserved for patients with severe hyperkalemia without hypertension and congestive heart failure.
The Renin Angiotensin Aldosterone Reflex
Aldosterone Synthase Deficiency ASD Congenital hypoaldosteronism is a rare inherited disorder transmitted as either an autosomal recessive or autosomal dominant trait with mixed penetrance. Patients with "corticosterone methyloxidase I CMO I " deficiency have elevated serum levels of corticosterone and low levels of hydroxycorticosterone and aldosterone. In contrast, patients with "corticosterone methyloxidase II CMO II " deficiency have high levels of hydroxycorticosterone, the immediate precursor of aldosterone With greater understanding of structure-activity relationships in the CYP11B2 enzyme, this disorder may be better considered a spectrum of hormonal deficiencies, depending on the nature of the CYP11B2 gene defect Because two steps of aldosterone biosynthesis from corticosterone previously proposed to be catalyzed by separate enzymes, CMO I and II, previously, are known to involve only one enzyme substarate interaction 6.
Isolated aldosterone deficiency results from loss of activity of aldosterone synthase encoded by CYP11B2 geneTherefore, the term aldosterone synthase deficiency type 1 ASD1 and type 2 ASD2 reflects more appropriately the molecular basis of this disease. In both ASD1 and 2, glomerulosa zone corticosterone is increased and aldosterone decreased, but hydroxycorticosterone is increased in ASD2 ASD1 is associated with loss of both hydroxilation and oxidation enzyme activities.
In ASD2, the ability to convert corticosterone B to hydorxytetrahydrodehydrocorticosterone OH-B is preserved with failure of further oxidation of hhdroxicorticosrerone to aldosterone The deficiency of aldosterone is much more severe in ASD1. In contrast, aldosterone may reach normal levels under intense stimulation of rennin-angiotensin system in ASD2 The clinical presentations of these deficiencies are otherwise similar. The clinical presentation is typical of aldosterone deficiency, including electrolyte abnormalities such as a variable degree of hyponatremia, hyperkalemia and metabolic acidosis, with poor growth in childhood, but they usually no symptoms in adults 83, In infants, it is characterized by recurrent dehydration, salt wasting and failure to thrive.
These symptoms are present generally within the first 3 months of life, and most often after the first 5 days of life. A modest uremia with a normal creatinine level reflects dehydration in the presence of intrinsically normal renal function. Plasma renin activity is invariably elevated. Diagnosis and Therapy The diagnosis can be established by measuring the appropriate corticosteroids or their major metabolic products, such as deoxycorticosterone DOCcorticosterone, hydroxycorticosterone, hydroxy-DOC and aldosterone levels in plasma.
Both forms of the syndrome are treated by replacement of mineralocorticoid with the usual dosage of fludrocortisone 0. Oral sodium supplementation may be discontinued once plasma rennin activity has decreased to normal, but mineralocorticoid replacement is usually maintained through childhood Molecular mechanisms of CYP11B2 deficiency Some patients with ASD1 CMO I deficiency have a homozygous 5 nucleotide deletion in exon 1 which leads to a frameshift and premature stop codon, resulting in the complete lack of enzyme production 84, This suggests that the arginine in aldosterone synthase is highly conserved and apparently quite important for enzyme activity.
The LF mutant protein in vitro showed complete aldosterone deficiency with deoxycirticosterone or corticosterone as substrates. The LF mutation located immediately adjacent to the highly conserved heme-binding C of the cytochrome P Computer modeling of the molecule suggested that this substitute my lead a steric effect resulting in preventing the activity of CYP11B2 The SP mutant protein in vitro showed complete loss of enzyme activity.
This mutated residue is likely to locate within the a-helix I, close to the heme-binding, active site of the enzyme. This structural change may be the cause of this disorder in this family Such patients are all homozygous for two mutations, RW in exon 3 and VA in exon 7 85,87,88, These mutations together reduce aldosterone synthase activity to 0.
The distinction between ASD 1 and ASD 2 is not precise, and these disorders should be regarded as different degrees of severity on a continuous clinical spectrum. W56X was inherited from his mother and RX was from his father. Since both alleles contain nonsense mutations, a lack of CYP11B2 activity was speculated to cause his condition Both healthy parents were heterozygous for all three substitutions.
Another female Italian Caucasian patient was a compound heterozygous mutation located in exon 4 causing a premature stop codon EX and a further mutation in exon 5 that also cause a premature stop codon QX. Arrows indicate direction of transcription.
Acquired form of primary hypoaldosteronism Several conditions may be associated with aldosterone biosynthetic defects. The administration of heparin causes natriuresis and hyperkalemia Heparin preparations suppress aldosterone synthesis, leading to a compensatory rise in plasma renin activity.
However, it has been demonstrated that this suppression of enzyme activity is attributable to chlorbutol 1,1,1-trichloromethylpropanolthe preservative used in commercial heparin, rather than to pure heparin Persistently hypotensive, critically ill patients with sepsis, pneumonia, peritonitis, cholangiitis and liver failure, also have inappropriately low plasma aldosterone concentrations in relation to elevated plasma renin activity The defect is at the level of the adrenal but has not been associated with any particular disease or therapy.
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- Renin–angiotensin system
Plasma cortisol levels are high, reflecting the stressed state. The response to angiotensin infusion is impaired, and the ratio of plasma hydroxycorticosterone to aldosterone is increased, suggesting selective insufficiency of CMO II. Because the filtration fraction has increased, there is less plasma fluid in the downstream peritubular capillaries. This in turn leads to a decreased hydrostatic pressure and increased oncotic pressure due to unfiltered plasma proteins in the peritubular capillaries.
The effect of decreased hydrostatic pressure and increased oncotic pressure in the peritubular capillaries will facilitate increased reabsorption of tubular fluid. Angiotensin II decreases medullary blood flow through the vasa recta. This decreases the washout of NaCl and urea in the kidney medullary space.
Thus, higher concentrations of NaCl and urea in the medulla facilitate increased absorption of tubular fluid. Furthermore, increased reabsorption of fluid into the medulla will increase passive reabsorption of sodium along the thick ascending limb of the Loop of Henle.
This will ultimately lead to increased sodium reabsorption. Angiotensin II stimulates the hypertrophy of renal tubule cells, leading to further sodium reabsorption.
CV Physiology | Renin-Angiotensin-Aldosterone System
In the adrenal cortexangiotensin II acts to cause the release of aldosterone. Aldosterone acts on the tubules e. This increases blood volume and, therefore, increases blood pressure. In exchange for the reabsorbing of sodium to blood, potassium is secreted into the tubules, becomes part of urine and is excreted.
Angiotensin II causes the release of anti-diuretic hormone ADH also called vasopressin — ADH is made in the hypothalamus and released from the posterior pituitary gland. The RAA pathway ensures that it will correct for all three of these triggers.
It makes this a very important reflex because it controls your blood pressure and your two most important minerals in your body: When Renin is secreted, it stimulates a protein in your blood stream called angiotensinogen. The liver makes most of these plasma proteins such as albumin.
This angiotensinogen is always circulating in the blood stream.
Renin–angiotensin system - Wikipedia
Renin activates it and turns it into angiotensin Your stomach cells secrete something called pepsinogen and the hydrochloric acid activates it into pepsin. During blood clotting, Fibrinogen is turned into fibrin. How does Renin activate Angiotensin? Angiotensinogen is a polypeptide. Renin cleaves four of the last amino acids in the molecule, and changes it to Angiotensin I, so to say it got activated, was to mean it got shorter."Long Distance Relationship" Poetry by shekhar  For all the long distance lovers 💏