BIOM3010 Renal Physiology 1

BIOM3010Renal Physiology 4Karen MoritzSchool of Biomedical Sciencesk.moritz@uq.edu.auReference: Sherwood, 8th edition, Chapter 14, p 534-540Chapter 15, 552-562

Learning ObjectivesUnderstand how the loop of Henle produces a vertical osmotic gradient to produce urine of varying concentrationsUnderstand the importance of regulating ECF osmolarity and volumeDescribe the hormonal control of salt and water balanceKnow the mechanisms of action of vasopressin and aldosterone, and their role in maintaining fluid homeostasis.Know the other hormones produced by the kidney Fluid balance and body waterBody water is distributed between the ICF and ECF. Approximately 2/3 of total body water is found in the ICF, with the remainder in the ECF (plasma and interstitial fluid)Regulating fluid balance is critical for maintaining homeostasis. This involves regulation of both ECF volume (including plasma volume) and ECF osmolarity.The kidneys play a vital role in regulating both of these factors. ECF volume is controlled by regulating salt balance. ECF volume regulation is important for maintaining blood pressure.ECF osmolarity is controlled by regulating water balance. ECF osmolarity must be regulated in order to prevent shrinkage or swelling of cells.The kidneys can produce dilute or concentrated urineThe kidneys need to be able to produce dilute or concentrated urine in order to maintain ECF osmolarity.

If the ECF is hypotonic, dilute urine needs to be produced to remove water and restore normal osmolarity.

If the ECF is hypertonic, the urine produced needs to be concentrated in order to conserve water.

The establishment of a vertical osmotic gradient in the loop of Henle by juxtamedullary nephrons enables the kidney to produce urine of varying concentrations (from 100 mOsm/L to 1200 mOsm/L).

Loop of Henle and countercurrent flowAt the end of the proximal tubule, ~ 35% of the filtered fluid (isotonic) remains. In the loop of Henle, an additional ~15% of the filtered water is reabsorbed, and the osmolarity of the tubular fluid altered.

The descending and ascending loops of Henle have functional distinctions that are critical for their ability to concentrate urine.

The descending limb is highly permeable to water due to constitutive expression of AQP1 water channels. It does not reabsorb Na+ (it is the only segment of the nephron that doesnt reabsorb Na+)

The ascending limb is impermeable to water, but actively reabsorbs Na+ from the tubular fluid (ie Na+ can leave without water following)Countercurrent flow: freeze frame

Before the vertical osmotic gradient is established, interstitial fluid and tubular fluid are isoosmotic (300 mOsm/L)

In the ascending limb, Na+ is actively pumped out of the tubular fluid into the interstitial fluid. This limb is impermeable to water, so the tubular fluid remains hypotonic. The descending limb is permeable to water, so water moves from the tubular fluid to the interstitium, making both hypertonic.Countercurrent flow: freeze frame

As fluid continues to flow through the tubule, the hypertonic fluid from the descending limb moves into the ascending limb, whilst isotonic fluid moves into the descending limb from the proximal tubuleCountercurrent flow: freeze frame

This once again creates a concentration difference between the two limbs of the loop.

The ascending limb continues to pump Na+ from the tubular fluid into the interstitial fluid. Water once again moves from the lumen of the descending limb into the interstitial space to equalise solute concentrations. Note that the concentration of the tubular fluid is increasing in the descending limb and decreasing in the ascending limb.Countercurrent flow: freeze frame

Fluid continues to flow into the loop of Henle from the proximal tubule, again creating a difference in concentration between the two limbs. Countercurrent flow: freeze frame

Active movement of Na+ out of the ascending limb and diffusion of water out of the descending limb continue to establish the vertical osmotic gradient. Countercurrent flow: The final picture

Ultimately, a vertical osmotic gradient of 300 1200 mOsm/L is established.

By establishing this osmotic gradient, the body can excrete a urine more concentrated than the isoosmotic body fluids.

Hormonal control of water reabsorption in the distal regions of the nephron allow for excretion of urine more dilute than isoosmotic body fluidsVasopressin controls active water reabsorptionThe distal tubule and collecting duct are usually impermeable to water. They become permeable to water in the presence of the hormone vasopressin.

Vasopressin (also known as antidiuretic hormone or ADH) is produced in the hypothalamus and stored in the posterior pituitary. Upon release into the circulation, vasopressin travels to the epithelial cells of the distal tubule and collecting duct, and increases permeability of these cells to water.Conditions of water deficit and excess:

Vasopressin controls active water reabsorption- dehydration

Vasopressin secretion is increased in response to a water deficit, increasing water permeability in the DT/CD.

The tubular fluid therefore loses fluid by osmosis as it progresses through this region of the nephron, leading to the excretion of concentrated urine.

The vertical osmotic gradient is essential for providing the driving force for water reabsorptionVasopressin controls active water reabsorption water excessVasopressin secretion is suppressed in response to a water excess, decreasing water permeability in the DT/CD.

This means that the tubular fluid cannot lose water as it passes through this region of the nephron, leading to excretion of dilute urine.

Vasopressin controls active water reabsorption

Vasopressin secretion is stimulated by water deficit .

This is detected by osmoreceptors in the hypothalamus (major mechanism) and volume receptors in the left atria.

Vasopressin secretion is thus triggered by an increase in ECF osmolarity or a large loss in ECF volume

Low ECF osmolarity and elevated ECF volume suppress vasopressin secretion.

Vasopressin controls active water reabsorption

After secretion, vasopressin binds to V2 receptors on the basolateral membrane of epithelial cells in the distal tubule/collecting duct.

V2 is a GPCR that couples to Gs, thus elevating cAMP.

Increased cAMP induces trafficking of aquaporin 2 (AQP-2) water channels to the luminal membrane.

Increased insertion of AQP-2 into the luminal membrane increases free water reabsorption.Diabetes insipidus

Diabetes insipidus is characterized by excessive thirst and production of large amounts of diluted urine.

DI can be caused by deficiencies in the vasopressin system, and the pathogenesis can be central or nephrogenic.

ECF volume and osmolarity can be changed independentlyDecreaseNo changeIncreaseIncrease

No changeNormal volume and osmolarityDecrease

OsmolarityVolumeECF volume and osmolarity can be changed independentlyDecreaseNo changeIncreaseIncrease

Drinking a large volume of waterNo change

Normal volume and osmolarityDecrease

OsmolarityVolumeECF volume and osmolarity can be changed independentlyDecreaseNo changeIncreaseIncrease

Drinking a large volume of waterIngesting isotonic salineNo change

Normal volume and osmolarityDecrease

OsmolarityVolumeECF volume and osmolarity can be changed independentlyDecreaseNo changeIncreaseIncreaseDrinking a large volume of waterIngesting isotonic salineEating salty food with liquid (~ hypertonic saline)No change

Normal volume and osmolarityDecrease

OsmolarityVolumeECF volume and osmolarity can be changed independentlyDecreaseNo changeIncreaseIncreaseDrinking a large volume of waterIngesting isotonic salineEating salty food with liquid (~ hypertonic saline)No change

Drinking water after sweat lossNormal volume and osmolarityDecreaseOsmolarityVolumeECF volume and osmolarity can be changed independentlyDecreaseNo changeIncreaseIncreaseDrinking a large volume of waterIngesting isotonic salineEating salty food with liquid (~ hypertonic saline)No change

Drinking water after sweat lossNormal volume and osmolarityEating salt without liquidsDecreaseOsmolarityVolumeECF volume and osmolarity can be changed independentlyDecreaseNo changeIncreaseIncreaseDrinking a large volume of waterIngesting isotonic salineEating salty food with liquid (~ hypertonic saline)No change

Drinking water after sweat lossNormal volume and osmolarityEating salt without liquidsDecreaseDehydration (sweat loss, diarrhoea)OsmolarityVolumeECF volume and osmolarity can be changed independentlyDecreaseNo changeIncreaseIncreaseDrinking a large volume of waterIngesting isotonic salineEating salty food with liquid (~ hypertonic saline)No change

Drinking water after sweat lossNormal volume and osmolarityEating salt without liquidsDecreaseHaemorrhageDehydration (sweat loss, diarrhoea)OsmolarityVolumeECF volume and osmolarity can be changed independentlyDecreaseNo changeIncreaseIncreaseDrinking a large volume of waterIngesting isotonic salineEating salty food with liquid (~ hypertonic saline)No change

Drinking water after sweat lossNormal volume and osmolarityEating salt without liquidsDecreaseIncomplete compensation for dehydration (uncommon)HaemorrhageDehydration (sweat loss, diarrhoea)OsmolarityVolumeNa+ reabsorption controls salt balance and ECF volumeRegulation of salt balance is a major determinant of ECF volume, and therefore controls long-term arterial pressure.

Renal conservation of Na+ leads to conservation of water (recall that most Na+ reabsorption occurs in an unregulated manner).

Active regulation of Na+ in the latter parts of the tubule is therefore a major determinant of Na+ output.

The renin-angiotensin-aldosterone system is a major regulator of Na+ reabsorption

Renin-angiotensin-aldosterone system

Aldosterone

Aldosterone is a steroid hormone. It binds to the mineralocorticoid receptor (MR) and increases the transcription of ENaC and Na-K pumps in the collecting tubule epithelia.

This increases Na+ reabsorption and K+ secretionPotassium reabsorption

Potassium secretion

Aldosterone is the major hormonal regulator of K+ secretion.

Increased plasma K+ directly stimulates aldosterone release from the adrenal cortex, whilst decreases in plasma K+ suppress aldosterone secretion.

Tight control of body K+ levels is vital as even small changes in plasma K+ can have detrimental effects, particularly on the heart.

SummaryThe loop of Henle uses a countercurrent mechanism to establish a vertical osmotic gradient that is essential for the ability of the kidney to produce urine that is more dilute or more concentrated than body fluids.Active control of water and salt balance is essential for the regulation of ECF osmolarity and volumeVasopressin is the major hormone responsible for regulating free water reabsorption (and therefore ECF osmolarity)Aldosterone is a steroid hormone that controls Na+ reabsorption (and therefore ECF volume)Aldosterone also causes K+ secretion and is a major regulator of plasma K+ levels.