Tubular reabsorption part 3

Reabsorption of nutrients, water and ions
The reabsorption of Na+ by primary active transport provides the  energy  and the means for reabsorbing almost every other substance, including water. Substances reabsorbed by secondary active transport (the "push" comes from the gradient  created by Na+K+ pumping at the basolateral membrane) include glucose, amino acids, lactate and vitamins. In nearly all these cases, a luminal carrier moves Na+ down its concentration  gradient as it cotransports (symports) another solute. Cotransported solutes diffuse (via different transport proteins) across the  basolateral membrane before moving into the peritubular capillaries. Although there is some overlap of carriers, the transport systems for the various solutes are quite  specific and limited.

There is a transport maximum (Tm) for nearly every substance that is reabsorbed using a transport protein in the membrane. The Tm (reported in mg/min) reflects the number of transport protein in the renal tubules available to ferry each particular substance. In general, there are plenty of transporters and therefore high Tm values for substances such as glucose that need to be retained, and few or no transporters for substances of no use to the body.

When the transportes are saturated,-that is, all bound to the substance they transport-the excess is excreted in urine. This is what happens in individuals who become hyperglycemic because of uncontrolled diabetes mellitus. As plasma levels of glucose approach and exceed 180 mg/dl, the glucose Tm is exceeded and large amounts of glucose may be lost in the urine even though the renal tubules are still functioning normally.

In passive tubular reabsorption, which encompasses osmosis, diffussion,  and facilitated diffusion, substances move down their electrochemical gradients without the use of ATP. The movement of Na+ and other solutes establishes a strong  osmotic gradient, and water moves by osmosis into the peritubular capillaries, a process aided by transmembrane proteins called aquaporins that form water channels across cell membrane. In continuosly water-permeable regions, aquaporins are constant components of the tubule cell membranes.  Because these channels are always present, the body is "obliged" to absorb water in the proximal nepron regardless of its state of over or underhydration. This water flow is referred to as obligatory water reabsorption. Aquaporins are virtually absent in the luminal membranes of the collecting duct unless antidiuretic hormone (ADH) is present.
As water leaves the tubules, the concentration of solutes in the filtrate increases and, if able, they to begin to follow their concentration gradients into the peritubular capillaries. This phenomenon of solutes following solvents explains the passive reabsorption of a  number  of solutes present in the filtrate, such as lipid-soluble substances, certain ions and some urea. It also explains in part why lipid-soluble drugs and enviromental toxins are difficult to excrete, since lipid-soluble compounds can generally pass through membranes, they will follow their concentration gradients and be reabsorbed, even if this is "not desirable".

As they move through the tubule cells into the  peritubular capillary blood, Na+ ions also establish an electrical gradient that favors passive reabsorption of anions (primarily Cl-) to restore electrical neutrality in the filtrate and plasma.

Any plasma proteins that squeeze through the filtration membrane are removed from the filtrate in the proximal tubule by endocytosis and digested to their amino acids, which are moved into the peritubular blood.

Tubular reabsorption part 2

SODIUM REABSORPTION (Na+)

Sodium ions (Na+) are the single most abundant cation in the filtrate, and about 80% of the energy is used for active transport is devoted to their reabsorption. Sodium reabsorption is almost always active and via the transcellular route.

In general, two basic processes that promote active Na+ reabsorption occur in each tubule segment.

First, Na+ is actively transported out of the tubule cell by primary active transport-a Na+K+ ATPase pump present in the basolateral membrane. From there,  Na+ is swept along by the bulk flow of the water into adjacent  peritubular capillaries is rapid because the blood there has low hydrostatic pressure and high osmotic pressure (remember, most protein remain in the blood instead of being filtered out into the tubule).

Second, active pumping of Na+ from the tubule cells result in a strong electrochemical  gradient that favors its passive entry at the luminal face via secondary active transport carries  or via facilitated diffusion through channels. This  occurs because (1)the pump maintains the intracellular Na+ concentrations at low levels (2)the K+  pumped into the tubule cells almost immediately diffuses out into the interstitial fluid via leakage channels, leaving the interior of the tubule cell with a net negative charge.
Because each tubule segment plays a slightly different  role in reabsorption, the precise mechanism by which Na+ is reabsorbed at the luminal membrane varies.

Tubular reabsorption part 1

Total plasma volume filters into the renal tubules about every 22 minutes, so all plasma  would be drained  away as urine in less than 30 minutes were it not for the fact that most of the tubule contents are quickly reclaimed  and returned to the blood. This reclamation process, called tubular reabsorption, is a selective transepithelial process that begins as soon as the filtrate enters the proximal tubules. To reach the blood, reabsorbed substances follow either  either the transcellular or paracellular route. In the transcelullar route, transported transported substances move through the luminal membrane, the cytosol, and the basolateral membrane of the tubule cell and then the endothelium of the peritubular capillaries.  Movement of substances in the paracellular route between the tubule cells is limited because these cells are connected by tight junctions. In the proximal nephrons, however, these tight junctions are "leaky" and allow some important ions (Ca^2+, Mg^2+, K⁺, and some Na⁺) through the paracellular route.

Given healthy  kidneys, virtually all organic nutrients  such as glucose and amino acids are completely reabsorbed to maintain or restore  normal plasma concentrations. On the other hand, the reabsorbtion of water and many ions  is continuosly regulated and adjusted in response to hormonal signals. Depending of the substances transported, the reabsortion process  may be passive (no ATP required) or active (at least one of its steps is driven by ATP directly or indirectly)

L I F E

To my son in heaven... We always love you... God loves you too...

Glomerular filtration part 2C

Other factors affecting Glomerular filtration rate
Renal cells produce a battery of chemicals, many of which act as paracrines (local signaling molecules) :

• Prostaglandin E2  (PGE2) : The vasodilatory paracrine PGE2, counteracts vasoconstriction by norepinephrine  and angiotensin II within the kidney. The adaptive value of these opposing actions is to prevent renal damage while responding to body demands to increase peripheral resistance

• Intrarenal angiotensin II : Although we usually think of angiotensin II as hormone, the kidney makes its own, locally acting angiotensin II that reinforces the effects of hormonal angiotensin II, It also dampens the resulting renal vasoconstriction by causing PGE2 release.

• Adenosine : Adenosine can be released as such or produced extracellularly from ATP released by macula densa cells. Although it functions as avasodilator systemically, adenosine constricts the renal vasculature

Abnormally low urine output (less than 50 ml/day), called anuria, may indicate that glomerular blood pressure is too low to cause filtration. However, renal failure and anuria can result from situations in which the nephrons cease to functions for a variety of other reason, including acute nephritis, transfusion reactions and crush injuries.

Glomerular filtration part 2B

EXTRINSIC CONTROLS (NEURAL AND HORMONAL MECHANISM)
The purpose of the  extrinsic controls regulating the glomerular filtration rate is to maintain systemic blood pressure - sometimes to the detriment of the kidneys.

• Symphatetic nervous system controls

Neural renal controls serve the needs of the body as a whole. When the volume of the extracellular fluid is normal and the sympathetic nervous system is at rest , the renal blood vessels are dilated and renal autoregulation mechanisms prevail. However, during extreme stress or emergency when it is necessary to shunt blood to vital organs, neural controls may overcome renal autoregulatory mechanisms.

Norepinephrine released by symphatetic nerve fibers  (and epinephrine released by the adrenal medulla) acts on alpha-adrenergic receptors on vascular smooth muscle, strongly constricting afferent arterioles, thereby inhibiting filtrate formation. This, in turn, indirectly trips the renin-angiotensin mechanism by stimulating the macula densa cells. The sympathetic nervous system also directly stimulates the granular cells to release renin.

• RENIN-ANGIOTENSIN MECHANISM

The renin-angiotensin mechanism is triggered when various stimuli cause the granular cells to release  the hormone renin. Renin acts enzymatically on angiotensinogen, a plasma globulin made by the liver, converting it  to angiotensin I. This, in turn, is converted to angiotensin II by angiotensin converting enzyme (ACE) associated with the capillary endothelium in various body tissues, particularly the lungs.

Angiotensin II acts in five ways to stabilize systemic blood pressure and extracellular  fluid volume. (1) As a potent vasoconstrictor , angiotensin II activates smooth muscle of arterioles throughout the body, raising mean arterial blood pressure. (2) Angiotensin II stimulates reabsorption of sodium, both directly by acting on renal tubules and indirectly by triggering the release of aldosterone from the adrenal cortex. Because water follows sodium osmotically, blood volume and blood pressure rise. (3) Angiotensin II stimulates the hypothalamus to release anti diuretic hormone and activates the hypothalamic thirst center, both of which increase blood volume. (4) Angiotensin II also increases fluid reabsorption by decreasing peritubular capillary hydrostatic pressure. This pressure drop occurs because the efferent arterioles constrict, and the downstream drop in hydrostatic pressure allows more fluid to move back into the peritubullar capillary bed. (5) Angiotensin II targets the glomerular mesangial cells, causing them to contract and reduce the glomerulus filtration rate by decreasing the total surface area of glomerular capillaries available for filtration.
While this seems daunting list at first, it will help that all of the effects of angiotensin II are aimed at restoring blood volume and blood pressure. Of angiotensin II's many effects, the first two are the most important.

Several factors acting independently or collectively can trigger renin release:

1. Reduced stretch of the granular cells. A drop in mean systemic blood pressure below 80 mmHg (as might be due to hemorrhage, dehydration, etc) reduces the stretch of the granular cells and stimulates them to release more renin
2. Stimulation of the granular cells by input from activated macula densa cells. When macula densa  cells sense low NaCl concentration (slowly moving filtrate), they signal the granular cells to release renin. This signal may decrease release of ATP (also thought to be the tubuloglomerular feedback messenger), increased release  of the prostaglandin PGE2, or both
3. Direct stimulation of granular cells via β1-adrenergic receptors by renal symphatetic nerves.

Glomerular filtration part 2A

Regulation of glomerular filtration
Glomerular filtration rate is regulated by both intrinsic and extrinsic controls. These two types of controls serve two different (and sometimes opposing) needs. The kidneys need a relatively constant glomerular filtration rate in order to do their job and maintain extracellular homeostasis. On the other hand,the body as the whole needs a constant blood pressure, and therefore a constant blood volume.
Intrinsic controls (renal autoregulation) act locally within the kidney to maintain glomerular filtration rate, while extrinsic controls by the nervous and endocrine systems maintain blood pressure. In extreme changes of blood pressure  (mean arterial pressure less than 80 or greater than 180 mmHg), extrinsic control take precedence over intrinsic controls.

INTRINSIC CONTROLS  (RENAL AUTOREGULATION)
By adjusting its own resistance to blood flow, a process called renal autoregulation, the kidney can maintain a nearly constant glomerular filtration rate despite fluctuations in systemic arterial pressure. Renal autoregulation entails two types of controls :

• Myogenic mechanism

The myogenic mechanism reflects the tendency of vascular smooth muscle to contract when stretched. Increasing systemic blood pressure causes the afferent arterioles to constrict, which restricts blood flow into the glomerulus and prevents glomerular blood pressure from rising to damaging levels. Declining systemic blood pressure causes dilatation of afferent arterioles and raises glomerular hydrostatic pressure. Both responses  help maintain a normal glomerular filtration rates.

• Tubuloglomerular feedback mechanism

Autoregulation by the flow-dependent tubuloglomerular feedback mechanism is "directed" by  the macula densa cells of the juxtaglomerular apparatus. These cells, located in the walls of the ascending limb of Henle's loop, respond to filtrate NaCl concentration (which varies  directly with filtrate flow rate). When glomerular filtration rate  increases, there is insufficient time for reabsorption and the concentration of NaCl in the filtrate remains high. This causes the macula densa cells to release a vasoconstrictor chemical (probably ATP) that causes intense constriction of the afferent arteriole. This constriction hinders blood flow into the glomerulus, which decreases the net filtration pressure and glomerulus filtration rate, allowing more time for filtrate processing (NaCl reabsorption),
On the other hand, when macula densa cells are exposed to slowly flowing filtrate with its low NaCl concentration, ATP release is inhibited, causing vasodilatation  of the afferent  arterioles. This allows more blood to flow  into the glomerulus, thus increasing net filtration presure and glomerulus filtration rate.

Autoregulatory mechanism maintain a relatively constant glomerulus filtration rate over an arterial pressure range from about 80 to 180 mmHg. Consequently, our normal day to day activity (such as exercise, sleep or changes in posture) do not cause large changes in water and solute excretion. However,  the intrinsic controls cannot handle extremely low systemic blood pressure, such as might result from serious hemorrhage (hypovolemic shock). Once the mean arterial pressure drops below 80 mmHg, autoregulation ceases.