UNC BIOL253 Exam 3 Study Guide

The Renal System

Functions of the Kidneys

1. Regulation of water, inorganic ion balance, and acid-base balance (in cooperation with the lungs)

2. Removal of metabolic waste products from the blood and their excretion in the urine

3. Removal of foreign chemicals from the blood and their excretion in the urine

4. Gluconeogenesis

5. Production of hormones/enzymes: Erythropoietin, renin, and conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D

Metabolic Waste Products from the Kidneys

1. Urea (from the catabolism of protein)

2. Uric acid (from nucleic acids)

3. Creatinine (from muscle creatine)

4. The end products of hemoglobin breakdown (which give urine much of its color)

Each nephron consists of:

• An initial filtering component called the renal corpuscle

• A tubule that extends from the renal corpuscle

Renal Tubule

A very narrow, fluid-filled cylinder made up of a single layer of epithelial cells resting on a basement membrane. The epithelial cells differ in structure and function along the length of the tubule.

1. Proximal convoluted tubule

2. Loop of Henle

   1. Descending limb

   2. Ascending limb

3. Distal convoluted tubule

4. Collecting-duct system

   1. Cortical collecting ducts

   2. Medullary collecting ducts

Renal Corpuscle

Forms a filtrate from blood that is free of cells, larger polypeptides, and proteins. This filtrate then leaves the renal corpuscle and enters the tubule.

The many capillaries in each corpuscle greatly increases the surface area for filtration of waste products from the plasma but their structure creates and efficient sieve for the ultrafiltration of plasma.

Each renal corpuscle consists of:

1. Glomerulus (a compact tuft of interconnected capillary loops)

2. Afferent arteriole (blood supplied to the glomerulus)

3. Bowman’s Capsule

4. Efferent arteriole (blood exiting the glomerulus)

Blood in the glomerulus is separated from the fluid in Bowman’s space by a filtration barrier consisting of three layers:

1. the single-celled capillary endothelium

2. a noncellular proteinaceous layer of basement membrane (also termed basal lamina) between the endothelium and the next layer

3. the single-celled epithelial lining of Bowman’s capsule

Podocytes

Epithelial cells in Bowman’s capsule that have an octopus-like structure in that they posses a large number of extensions, or foot processes.

Why is the renal circulation system unusual?

It includes two sets of arterioles and two sets of capillaries

• Afferent & efferent arterioles

• Glomerular & peritubular capillaries

Loop of Henle

• Major Functions: Establishes medullary osmotic gradient (juxtamedullary nephrons), secretion of urea, bulk reabsorption of water (descending limb), reabsorption of NaCl (ascending limb)

• Controlling Factors: passive water reabsorption & active transport driving reabsorption by cotransport

Vasa recta

Long capillary loop that runs next to the loop of Henle

Juxtamedullary Nephrons

Their renal corpuscle is located in cortex just next to the medulla, and they have long loops of Henle that dive deep into the medulla

Cortical Nephrons

Makes up ~85% of all nephrons, and they have short loops of Henle

Juxtaglomerular Apparatus

Composed of the macula densa and the juxtaglomerular cells

• Macula densa: patch of tubular wall cells at the end of the ascending limb of the loop of Henle

• JG cells: afferent arteriole wall cells that secrete renin

Glomerular Filtration

Urine formation begins with the filtration of plasma from the glomerular capillaries into Bowman’s space. The filtrate produces is called the glomerular filtrate. It’s cell-free and, except for larger proteins, contains all the substances including some polypeptides in virtually the same concentrations as in plasma.

Simplified: filtered plasma from glomerular capillaries into Bowman’s space

Tubular Reabsorption

When the direction of movement of the filtration is from the tubular lumen to the peritubular capillary plasma

Simplified: tubular lumen → capillary plasma

Secretion

Peritubular capillary plasma to tubular lumen

The amount of any substance excreted is equal to…?

The amount of substance filtered plus the amount secreted minus the amount reabsorbed

What forces are involved in capillary filtration?

1. hydrostatic pressure

2. osmotic forces

3. colloid pressures

Starling Forces

• The hydrostatic pressure difference across the capillary wall that favors filtration

• The protein concentration difference across the wall that creates an osmotic force that opposes filtration

Glomerular Capillary Hydrostatic Pressure P_GC

A force favoring filtration → it favors fluid movement out of the glomerular capillaries into Bowman’s space

It’s 60 mmHg and is considerably higher than most capillaries.

Bowman’s Space Hydrostatic Pressure P_BS

Exerts a hydrostatic pressure that opposes filtration

15 mmHg

Osmotic Force π_GC

Opposes filtration and results from the presence of protein in the glomerular capillary plasma. There is usually no protein in the filtrate in Bowman’s space, so the osmotic force in Bowman’s space is zero

29 mmHg

Net Glomerular Filtration Pressure

P_GC - P_BS - π_GC = net glomerular filtration pressure

Normally a positive value because the glomerular capillary hydrostatic pressure P_GC is larger than the sum of the hydrostatic pressure in Bowman’s space P_BS and the osmotic force opposing filtration π_GC

Initiates urine formation by forcing an essentially protein-free filtrate of plasma out of the glomerulus and into Bowman’s space and then down the tubule into the renal pelvis

Glomerular Filtration Rate (GFR)

The volume of fluid filtered from the glomeruli into Bowman’s space per unit time

At any given net filtration pressure, the GFR will be directly proportional to the membrane permeability and the surface area

Constriction of the afferent arterioles causes…?

Decreases in hydrostatic pressure in the glomerular capillaries (P_GC)

Efferent arteriole constriction causes…?

Increases in the hydrostatic pressure of the glomerular capillaries (P_GC)

Reabsorption by Mediated Transport

Many solutes are reabsorbed by primary or secondary active transport. These substances must first cross the apical membrane that separates the tubular lumen from the cell interior. Then, the substance diffuses through the cytosol of the cell and, finally, crosses the basolateral membrane, which begins at the tight junctions and constitutes the plasma membrane of the sides and base of the cell.

Why is the osmotic force mmHg of renal arteries higher than elsewhere in the body?

Enough water filters out of the glomerular capillaries that the protein remaining becomes slightly more concentrated than arterial plasma.

Hematuria

Blood in the urine; there should not be any red blood cells in the urine!

Transport Maximum

Exhibited by substances moved by mediated transporters. If the filtered load of a substance exceeds the resorptive transport maximum, the substance will be excreted in the urine.

Renal Clearance

The volume of plasma completely cleared of a substance per unit time. The basic clearance formula for any substance S is:

Clearance of C_S = U_SV / P_S

• C_S = clearance of S

• U_S = urine concentration of S

• V = urine volume per unit time

• P_S = plasma concentration of S

Why are C_s and U_s not the same?

They are not the same because the amount of substance in the urine less than what was filtered. This happens because of reabsorption, and also because a small of substance is absorbed from tubular cell metabolism.

Clearance of Glucose

C_gl = (0)(V) / P_gl = 0

C_gl = clearance of glucose

All of the glucose filtered from the plasma into Bowman’s space is normally reabsorbed by the epithelial cells of the proximal tubules.

When might the clearance of glucose not be zero?

when the concentration of glucose in the blood exceeds the kidney's reabsorption capacity

Consider a substance that is freely filtered, but not reabsorbed or secreted. Why might this be useful for making a diagnosis?

A substance like this would be useful for making a diagnosis because if you know the value of how much is supposed to be in the urine, and there is a different value when the test is performed, there could be an issue with the kidneys.

Creatinine Clearance (CCr)

Creatinine is a waste product released by muscle cells; it is filtered at the renal corpuscle but does not undergo reabsorption. It does undergo a small amount of secretion, so that some peritubular plasma is cleared of its creatinine by secretion.

• Used to approximate the GFR

• An increase in creatinine concentration in the blood usually indicates a decrease in GFR

Consider a scenario where all of substance Y is filtered but some remains in the plasma. What does this mean in terms of tubular activity?

It means some of substance Y was reabsorbed from the tubules.

Inulin

Small carbohydrate that is filtered but no reabsorbed or secreted; infused experimentally; clearance rate equals GFR

Filter load should equal amount excreted in urine

GFR of Inulin

U_inV / P_in

When clearance/excretion of a substance is greater than GFR, what must occur?

Secretion

Renal Plasma Flow

Estimated by the clearance of a substance (e.g., infused para-aminohippurate [PAH]) that is filtered, not reabsorbed, and 100% secreted. All that enters the kidneys from the blood is cleared.

Micturition

Urine in the bladder intermittently ejected during urination

What happens during the spinal reflex component of micturition?

1. As the bladder fills with urine, the pressure within it increases, which stimulates stretch receptors in the bladder wall

2. The afferent neurons from these receptors enter the spinal cord and stimulate the parasympathetic neurons, which then cause the detrusor muscle to contract

3. When the detrusor muscle contracts, the change in shape of the bladder pulls open the internal urethral sphincter. Simultaneously, the afferent input from the stretch receptors reflexively inhibits the sympathetic neurons to the internal urethral sphincter, which further contributes to its opening.

4. In addition, the afferent input also reflexively inhibits the somatic motor neurons to the external urethral sphincter, causing it to relax.

5. Both sphincters are now open, and the contraction of the detrusor muscle can produce urination

Chemoreceptors vs. Baroreceptors

• Baroreceptors have stretch receptors and regulate short-term blood pressure

• Chemoreceptors regulate pH, O₂, CO₂, and H⁺

Peripheral chemoreceptors respond when…

There is decreased P_O2 and increased H⁺

Central (medullary) chemoreceptors respond when…

There is increased H⁺ and increased CO₂

The reflex mechanisms controlling ventilation prevent _____ increases in arterial PCO2 to a much greater degree than they prevent ______ decreases in arterial PO2

small, equivalent

Filter load

GFR x plasma concentration of substance

This is important because it determines the net tubular reabsorption or net secretion of the kidneys. These levels could indicate some sort of issue.

What happens if a blood clot occurs in an afferent arteriole?

There would be no blood entering the glomerulus, and there would be less net filtration.

How might knowing about the filter load help diagnose disease?

If the filter load was low, that could indicate that the kidneys are not working properly. You can compared net secretion or net absorption to normal values.

What are the most important secreted substances?

Na⁺ and K⁺

What occurs when the detrusor muscle receives parasympathetic stimulation?

It causes the detrusor to contract. During filling, the parasympathetic signaling is inhibited and during micturition it’s stimulated.

What is the internal urethral sphincter innervated by?

The sympathetic nervous system.

When is the internal urethral sphincter stimulated by the sympathetic nervous system?

During filling

What is the external urethral sphincter innervated by?

The somatic motor system

When is the external urethral sphincter stimulated by the somatic motor system?

During filling

Urge

Associated with the desire to urinate (possibly because of a bacterial infection)

Stressors in Micturition

Sneezing, coughing, exercise

Treatment of incontinence

Anticholinergic drugs (which may cause tachycardia)

You lose water from 4-5 sites on the body. Where?

Skin, respiratory airways, gastrointestinal tract, urinary tract, and menstruation

Insensible water loss

Sweat, respiration

Coupling of H₂O and Na⁺ Reabsorption

• H₂O and Na⁺ both filter freely in the glomerulus

• H₂O and Na⁺ both get almost 99% reabsorbed

• 2/3 bulk reabsorption in the proximal convoluted tubule

• Na⁺ reabsorption is ACTIVE in all tubule segments except the descending loop of Henle

• H₂O reabsorption is PASSIVE via osmosis and dependent on Na⁺ reabsorption

Steps of Na⁺ & H₂O Reabsorption

1. Na+ is transported from tubular lumen into interstitial fluid across the epithelial cells. Other solutes (glucose, amino acids, HCO3) whose reabsorption depends on Na+ transport, also contribute to osmosis

2. Removal of solutes from tubular lumen decreases local osmolarity of tubular fluid adjacent to cell (local water concentration increases). Simultaneously, appearance of solute in interstitial fluid just outside the cell increases local osmolarity (local water concentration decreases)

3. Difference in water concentration between lumen and interstitial fluid causes net diffusion of water from lumen across the tubular cells’ plasma membranes and/or tight junctions into interstitial fluid

4. Water, Na+, and everything else dissolved in interstitial fluid move together by bulk flow into peritubular capillaries

When can water movement across the tubular epithelium occur?

Only when the epithelium is permeable to water. No matter how large its concentration gradient, water cannot cross an epithelium impermeable to it.

Where is water permeability under physiological control?

Cortical and medullary collecting ducts

Proximal Convoluted Tubule Reabsorption

• Na+ reabsorption is an active process

• Apical entry of Na+ occurs by cotransport with glucose or by countertransport with H+

• Primary active transport on the basal side

• Secondary active transport on the apical side

• Keeps intracellular concentrations low

• Na+ reabsorption derives the reabsorption of the cotransported substances and the secretion of H+

Ascending Loop of Henle Reabsorption

• Na⁺ reabsorption is an active process

• Main function = SODIUM REABSORPTION (not water)

  • Ascending limb is relatively impermeable to water

• NKCC (sodium, potassium, 2 chloride) cotransporter

  • depends on the Na+ concentration gradient generated by the basolateral Na+/K+-ATPase pump

• K+ absorbed through NKCC from tubular lumen is then recycled back to tubular lumen through apical K+ channels

• Cl- absorbed into interstitial fluid via basolateral chloride channel

• Primary active transport on the basal side

Descending Loop of Henle Reabsorption

• Highly permeable to WATER, does not reabsorb NaCl

• Net diffusion of water occurs out of the descending limb into the more concentrated interstitial fluid until the osmolarities are equal

Reabsorption of H₂O

• Coupled with Na⁺

• Water follows as long as the apical membrane is permeable

• OSMOSIS

Collecting Ducts Reabsorption

• Apical entry step for Na+ occurs primarily by diffusion via Na+ channels

Apical Na⁺ Entry Step

Movement of Na⁺ downhill from lumen into cell across the apical membrane varies from one segment of the tubule to another

Basolateral Na⁺ Exit Step

The basolateral membrane step is the same in all Na+-reabsorbing tubular segments- the primary active transport of Na+ out of the cell is via Na+/K+-ATPase pumps in the membrane

• It’s this transport process that decreases intracellular Na+ concentration and makes the downhill apical entry step possible

Vasopressin / Antidiuretic Hormone (ADH)

The major determinant of the controlled permeability of the tubular epithelium to water and the passive water reabsorption in the collecting ducts. It stimulates the insertion into the apical membrane of a particular aquaporin water channel made by collecting-duct cells.

High levels of vasopressin cause…

Dramatic increase in water permeability of the collecting ducts → passive water reabsorption is maximal and the final urine volume is small (less than 1% of filtered water)

Steps of Vasopressin Function

1. Vasopressin binding to its receptor increases intracellular cAMP via activation of a Gs protein and subsequent activation of adenylate cyclase

2. cAMP increases the activity of protein kinase A (PKA)

3. PKA increases the phosphorylation of specific proteins that increases the rate of the fusion of vesicles with the apical membrane

4. This leads to an increase in the number of AQP2 channels in the apical membrane

5. This allows increases passive diffusion of water into the cell

What happens when there is no vasopressin?

The water permeability of the collecting ducts is extremely low because the number of aquaporins in the apical membrane is minimal and very little water is reabsorbed from these sites

• Result: a large volume of water remains behind in the tubule to be excreted in the urine

Water diuresis

Increased urine excretion resulting from low vasopressin

Diabetes insipidis

A distinct form of diabetes caused by the failure of axons with cell bodies in the hypothalamus and synapses on blood vessels in the posterior pituitary to synthesize or release vasopressin, or the inability of the kidneys to respond to vasopressin

Hyperosmotic

The urine is concentrated relative to plasma

How does the medullary interstitial fluid become hyperosmotic?

• The countercurrent anatomy of the loop of Henle of juxtamedullary nephrons

• Reabsorption of NaCl in the ascending limps of those loops of Henle

• Impermeability to water of those ascending limbs

• Trapping of urea in the medulla

• Hairpin loops of vasa recta to minimize washout of the hyperosmotic medulla

What is the osmolarity of the fluid entering the cortical collecting duct, regardless of the plasma concentration of vasopressin?

Hypoosmotic

Osmotic diuresis

Water loss in the urine due to excessive solute excretion

Obligatory water loss

minimal volume of water loos (~0.44 L/day)

Vasa recta

hairpin-loop blood vessels that prevent the countercurrent gradient (created by the loops of Henle) from being washed away

What responses regulate urinary Na+ excretion?

Various cardiovascular baroreceptors (e.g., carotid sinus) and by sensors in the kidneys that monitor the filtered load of Na+

Regulation of cardiovascular pressures by baroreceptors also simultaneously achieves regulation of total-body ______

Sodium

What does the amount of Na+ in the body determine?

• Extracellular fluid volume

• Plasma volume component which helps determine cardiovascular pressures

• Responses that control Na+ excretion

What is the main factor in determining that rate of tubular Na+ reabsorption?

Aldosterone

Aldosterone

• Steroid hormone produced by the adrenal cortex that acts slowly because it induces changes in gene expression & protein synthesis

• Stimulates Na+ reabsorption by the distal convoluted tubule and the cortical collecting ducts

• Low levels = Na+ excreted

• High levels = all Na+ reaching the DCT and CCD is reabsorbed

• Induces synthesis of ion channels & pumps in CCD

Which organ produces angiotensinogen?

Liver

Angiotensin-converting enzyme (ACE)

• Cleaves angiotensin I to form the active agent of the RAAS system; angiotensin II

• Found in very high concentration on the apical surface of capillary endothelial cells

Renin

• Enzyme secreted by the juxtaglomerular cells of the juxtaglomerular apparatuses in the kidneys

• Splits a small polypeptide, angiotensin I, from a large plasma protein, angiotensinogen

Angiotensin II

• Stimulates secretion of aldosterone

• Very powerful vasoCONSTRICTOR → increases arterial pressure

• High levels during NaCl depletion

• Low levels during high NaCl intake

What effect would an ACE inhibitor have on renin secretion and angiotensin II production?

It would decrease angiotensin II production. The resultant increase in Na+ and water excretion would decrease BP, leading to a reflexive increase in renin secretion

What is the rate-limiting factor in angiotensin II formation?

Plasma renin concentration

What are the mechanisms by which sodium depletion causes an increase in renin secretion?

• Renal sympathetic nerves

• Intrarenal baroreceptors

• Macula densa

Atrial natriuretic peptide (ANP)

• Synthesized and secreted by cardiac atria

• Acts on several tubular segments to INHIBIT Na+ reabsorption

• Can act on renal blood vessels to increase GFR, furthering contributing to increase Na+ (and water) excretion

• Directly inhibits aldosterone secretion, leading to increased Na+ excretion

• High levels when there is excessive sodium in the body

• Secretion increases because of expansion of plasma volume that accompanies an increase in body sodium

Increased blood pressure decreases Na+ reabsorption by which two mechanisms?

• Inhibition of the RAAS activity

• Acts locally on renal tubules

Pressure natriuresis

Arterial pressure acts locally (directly) on the renal tubules; increased pressure causes decreased Na+ reabsorption (increases excretion)