Question

Fully explain the intrinsic regulation of glomerular filtration rate (GFR) and the extrinsic regulators (hormones) that regulate urinary function (GFR, reabsorption and excretion of Na+, and urine output) and thirst for the control of blood volume and blood pressure.

Answer 1

Glomerular Filtration

Filtrate is produced by the glomerulus when the hydrostatic pressure produced by the heart pushes water and solutes through the filtration membrane. Glomerular filtration is a passive process as cellular energy is not used at the filtration membrane to produce filtrate.

Glomerular filtration has to be carefully and thoroughly controlled because the simple act of filtrate production can have huge impacts on body fluid homeostasis and systemic blood pressure. Due to these two very distinct physiological needs, the body employs two very different mechanisms to regulate GFR. The kidney can control itself locally through intrinsic controls, also called renal autoregulation. These intrinsic control mechanisms maintain filtrate production so that the body can maintain fluid, electrolyte, and acid-base balance and also remove wastes and toxins from the body. There are also control mechanisms that originate outside of the kidney, the nervous and endocrine systems, and are called extrinsic controls. The nervous system and hormones released by the endocrine systems function to control systemic blood pressure by increasing or decreasing GFR to change systemic blood pressure by changing the fluid lost from the body.

Intrinsic Controls: Renal Autoregulation

The kidneys are very effective at regulating the rate of blood flow over a wide range of blood pressures. Your blood pressure will decrease when you are relaxed or sleeping. It will increase when exercising. Yet, despite these changes, the filtration rate through the kidney will change very little. The kidney’s ability to autoregulate can maintain GFR with a MAP of as low as 80 mm Hg to as high as 180 mm Hg. This is due to two internal autoregulatory mechanisms that operate without outside influence: the myogenic mechanism and the tubuloglomerular feedback mechanism.

Arteriole Myogenic Mechanism

The myogenic mechanism regulating blood flow within the kidney depends upon a characteristic shared by most smooth muscle cells of the body. When you stretch a smooth muscle cell, it contracts; when you stop, it relaxes, restoring its resting length. This mechanism works in the afferent arteriole that supplies the glomerulus and can regulate the blood flow into the glomerulus. When blood pressure increases, smooth muscle cells in the wall of the arteriole are stretched and respond by contracting to resist the pressure, resulting in little change in flow. This vasoconstriction of the afferent arteriole acts to reduce excess filtrate formation, maintaining normal NFP and GFR. Reducing the glomerular pressure also functions to protect the fragile capillaries of the glomerulus. When blood pressure drops, the same smooth muscle cells relax to lower resistance, increasing blood flow. The vasodilation of the afferent arteriole acts to increase the declining filtrate formation, bringing NFP and GFR back up to normal levels.

Tubuloglomerular Feedback

The tubuloglomerular feedback mechanism involves the juxtaglomerular (JG) cells, or granular cells, from the juxtaglomerular apparatus (JGA) and a paracrine signaling mechanism utilizing ATP and adenosine. These juxtaglomerular cells are modified, smooth muscle cells lining the afferent arteriole that can contract or relax in response to the paracrine secretions released by the macula densa. This mechanism stimulates either contraction or relaxation of afferent arteriolar smooth muscle cells, which regulates blood flow to the glomerulus . Recall that the DCT is in intimate contact with the afferent and efferent arterioles of the glomerulus. Specialized macula densa cells in this segment of the tubule respond to changes in the fluid flow rate and Na+ concentration.

As GFR increases, there is less time for NaCl to be reabsorbed in the PCT, resulting in higher osmolarity in the filtrate (hyperosmotic). The increased fluid movement more strongly deflects single nonmotile cilia on macula densa cells. This increased osmolarity of the filtrate, and the greater flow rate within the DCT, activates macula densa cells to respond by releasing ATP and adenosine (a metabolite of ATP). ATP and adenosine act locally as paracrine factors to stimulate the myogenic juxtaglomerular cells of the afferent arteriole to constrict, slowing blood flow into the glomerulus. This vasoconstriction causes less plasma to be filtered, which decreases the glomerular filtration rate (GFR), which gives the tubule more time for NaCl reabsorption. Conversely, when GFR decreases, less NaCl is in the filtrate, and most will be reabsorbed before reaching the macula densa, which will result in decreased ATP and adenosine, allowing the afferent arteriole to dilate and increase GFR. This vasodilation causes more plasma to be filtered, which increase the glomerular filtration rate (GFR), which gives the tubule less time for NaCl reabsorption increasing the amount of NaCl in the filtrate.

Extrinsic Controls: Neural and Hormonal Mechanisms

The extrinsic control mechanisms have an effect on GFR, but their primary function is to maintain systemic blood pressure. While the intrinsic controls functioned to specifically control GFR at the level of the kidneys, the neural and hormonal controls have a broader scope and function to meet the whole body’s needs, not just the needs of the kidneys.

Sympathetic Nerves

The kidneys are innervated by the sympathetic neurons of the autonomic nervous system via the celiac plexus and splanchnic nerves. Reduction of sympathetic stimulation results in vasodilation and increased blood flow through the kidneys during resting conditions. When the frequency of action potentials increases, the arteriolar smooth muscle constricts (vasoconstriction), resulting in diminished glomerular flow, so less filtration occurs. Under conditions of stress, sympathetic nervous activity increases, resulting in the direct vasoconstriction of afferent arterioles (norepinephrine effect) as well as stimulation of the adrenal medulla. The adrenal medulla, in turn, produces a generalized vasoconstriction through the release of epinephrine. This includes vasoconstriction of the afferent arterioles, further reducing the volume of blood flowing through the kidneys. This process redirects blood to other organs with more immediate needs. Under severe stress, such as significant blood loss, the sympathetic nervous system kicks into high gear to keep the blood routed to essential organs and keep the body alive. The strong vasoconstriction required to maintain systemic blood pressure under these severe conditions significantly reduces blood flow to the kidneys and can be damaging to the kidney tissues. If blood pressure falls, the sympathetic nerves will also stimulate the release of renin which we will discuss next.

Renin–Angiotensin–Aldosterone Mechanism

Recall that renin is an enzyme that is produced by the granular cells of the afferent arteriole at the JGA. It enzymatically converts angiotensinogen (made by the liver, freely circulating) into angiotensin I. Its release is stimulated by paracrine signals from the JGA in response to decreased extracellular fluid volume.

Angiotensin-converting enzyme (ACE) enzymatically converts inactive angiotensin I into active angiotensin II. ACE is not a hormone but it is functionally important in regulating systemic blood pressure and kidney function. It is produced in the lungs but binds to the surfaces of endothelial cells in the afferent arterioles and glomerulus. ACE is important in increasing blood pressure and this is why people with high blood pressure are sometimes prescribed ACE inhibitors to lower their blood pressure.

Angiotensin II is a potent vasoconstrictor that plays an immediate role in the regulation of blood pressure. It acts systemically to cause vasoconstriction as well as constriction of both the afferent and efferent arterioles of the glomerulus. Under the influence of Angiotensin II, the efferent arteriole constricts more strongly than the afferent arteriole, increasing GFR. In instances of blood loss or dehydration, Angiotensin II reduces both GFR and renal blood flow, thereby limiting fluid loss and preserving blood volume. Its release is usually stimulated by decreases in blood pressure, and so the preservation of adequate blood pressure is its primary role.

Aldosterone, often called the “salt-retaining hormone,” is released from the adrenal cortex in response to angiotensin II or directly in response to increased plasma K+. It promotes Na+ reabsorption by the nephron, promoting the retention of water. It is also important in regulating K+, promoting its excretion. (This dual effect on two minerals and its origin in the adrenal cortex explains its designation as a mineralocorticoid.) As a result, renin has an immediate effect on blood pressure due to angiotensin II–stimulated vasoconstriction and a prolonged effect through Na+ recovery due to aldosterone. At the same time that aldosterone causes increased recovery of Na+, it also causes greater loss of K+. Progesterone is a steroid that is structurally similar to aldosterone. It binds to the aldosterone receptor and weakly stimulates Na+ reabsorption and increased water recovery. This process is unimportant in men due to low levels of circulating progesterone. It may cause increased retention of water during some periods of the menstrual cycle in women when progesterone levels increase.

Antiduretic hormone (ADH) promotes the recovery of water, decreases urine volume, and maintains plasma osmolarity and blood pressure. It does so by stimulating the movement of aquaporin proteins into the apical cell membrane of principal cells of the collecting ducts to form water channels, allowing the transcellular movement of water from the lumen of the collecting duct into the interstitial space in the medulla of the kidney by osmosis. From there, it enters the vasa recta capillaries to return to the circulation. Water is attracted by the high osmotic environment of the deep kidney medulla. This process allows for the recovery of large amounts of water from the filtrate back into the blood. In the absence of ADH, these channels are not inserted, resulting in the excretion of water in the form of dilute urine. The function of aquaporins is to allow the movement of water across the lipid-rich, hydrophobic cell membrane.