Renin angiotensin aldosterone mechanism and its pathology

Renin-angiotensin and aldosterone system also known as RAAS is one of the major regulatory systems of the human body. It plays a major role in maintaining blood pressure and volume and regulating blood sodium levels. 

Mechanism of secretion of renin:  

Renin is an enzyme/hormone that is secreted by extra glomerular mesangial cells/Polkessien cells or juxtaglomerular granular cells. These cells are present in afferent arteriole of each nephron of kidneys and some in efferent arteriole too. They are the specialized smooth muscle which secrete renin whenever blood flow is less. 

When there is normal blood flow, there is normal filtration on the glomerulus, about 60% of sodium is reabsorbed and 25% is reabsorbed in the ascending loop of Henle. The remaining 10% remains in the distal convoluted tubule (DCT). In the DCT there are specialized cuboidal cells called macula densa cells which detect the concentration of sodium ions in the DCT.  

Juxtaglomerular apparatus: Nephron contain macula densa cells which are held together with Polkeisssien cells and juxtaglomerular granular cells by the connective tissue cells called lacis cells.

 

Local response: 

When there is less blood flow in the kidney i.e., decreased perfusion; the GFR decreases. As a result, there is slow movement of allowing reabsorption of sodium in higher rates in the PCT and ascending loop of Henle. Less than normal sodium reaches macula densa cells. This causes macula densa cells to release prostaglandins and nitric oxide which stimulate Polkeissen cells to release renin. 

Systemic response:  

When blood pressure decreases, the carotid sinus detects decreased blood pressure and send impulse via glossopharyngeal nerve which in turn sends impulse to the vasomotor center in the medulla. Stimulation of vasomotor center causes release of the sympathetic impulse via spinal cord to the sympathetic ganglion. The post ganglionic fibers of macula densa cells release norepinephrine activating beta-1 adrenergic receptors causing release of nitric oxide and prostaglandins which in turn stimulate Polkessien cells to release renin. 

 

The fate of renin: 

Renin released in the blood goes to the systemic circulation to the liver where it converts angiotensinogen produced by the hepatocytes into angiotenin-1.  

 

The fate of angiotensin-1: 

Angiotensin-1 is converted to angiotensin-2 by the angiotensin-converting enzyme (ACE). ACE is an ectopeptide which is present in the surface of endothelial cells of the lungs. 

 ACE also inactivates bradykinin which is a vasodilator. 

Angiotensin-2 is a powerful vasoconstrictor. 

 

Mechanism of action of angiotensin-2: 

The action of smooth muscles of blood vessels:

 

On venous smooth muscles: 

Angiotensin-2 causes constriction of venous smooth muscles which helps in increasing blood pressure. 

Constriction of smooth muscles in vein- increased blood flow to heart- increased venous return- increased end-diastolic volume- increased end-diastolic pressure- increased preload in the heart- increased stroke volume- increased cardiac output- increased systolic blood pressure. 

Action on arterial smooth muscles: 

Angiotensin-2 causes constriction of arterial smooth muscles which helps in increasing blood pressure. 

Constriction of arterial smooth muscles- constriction of arteries – increased blood flow resistance- retaining of blood – increased end-diastolic volume- increased diastolic blood pressure 

Release of aldosterone and sodium reabsorption:

Angiotensin-2 acts on the receptors of zona glomerulosa cells of adrenal cortex causing the release of aldosterone – aldosterone acts on the principal cells of the distal convoluted tubule and collecting tubule – it binds to the aldosterone operated receptors inside the cell – aldosterone receptor complex activates the gene that helps in the synthesis of Na+/K+ ATPase – this ATPase activity pumps a large amount of sodium out to the interstitial space – also the receptor complex activates gene which forms sodium channels in the luminal membrane – the deficit in the sodium causes absorption of sodium in large amount in the luminal membrane as the deficit is maintained by the ATPase activity in the basolateral membrane – again a 3rd gene is also activated which helps in the formation of potassium channels in the luminal membrane – along with sodium large amount of water is also reabsorbed -  this retained sodium and water helps in maintaining blood volume.

 

Release of ADH: 

When blood pressure and volume decreases, GFR decreases causing a rise in increased medullary osmolarity. 

Angiotensin-2 acts on the supraoptic nucleus of the hypothalamus – it stimulates the posterior pituitary to release antidiuretic hormone (ADH) - it binds with G protein-linked receptors which in turn activate adenylyl cyclase forming water channels called aquaporins in DCT and CT – the medullary interstitial hyperosmolarity causes osmosis of water from lumen to interstitium which as a result causes water reabsorption. 

 

 

Angiotensin-2 is a potent sympathetic stimulator: 

It increases central sympathetic outflow 

 

1. 1.Stimulates sympathetic ganglionic fibers 

2. 2.Increase secretion of norepinephrine in the synaptic junction and decreases its reabsorption 

3. 3.It causes increase in adrenergic receptor concentration in the target tissue 

4. 
   

Increased sympathetic response also causes arterial and venous constriction, secretes adrenaline, stimulates thirst center and in overall helps in retention of normal fluid volume and blood pressure. 

 

Pathology associated with RAAS: 

In patients with congestive cardiac disease, there is less renal perfusion. This activates RAAS mechanism indefinitely causing release of large amount of angiotensin-2 and aldosterone. Angiotensin-2 in large amount cause activation of protooncogenes which direct formation of more protein and muscle fibers. This causes alterations in shape and size of the heart called cardiac remodeling. This hypertrophic changes in the heart leads to progressive cardiac failure. 

Prolonged secretion of angiotensin-2 also leads to renal fibrosis, chronic renal disease, hypertension, obesity, vasculopathy, insulin intolerance, glaucoma and cataract. 

 

ACE inhibitors are the drugs of choice for better prognosis in the patients of CCF as they prevent prolonged secretion of angiotensin-2 and aldosterone.