patho2: mod1: lecs 1-3

renin

renin

• a protein enzyme release by the kidneys in response to blood pressure

• catalyzes the production of angiotensin, a hormone that causes arterioles to constrict, raising blood pressure

  • cleaves angiotensin to angiotensin I

• it also leads to water retention

homeostasis of the renal system

• controls the production of red blood cells

• remove waste products and toxins from the body (also certain medications)

• regulates the body’s fluid status (blood pressure), electrolyte balance, and acid-base balance

• release hormones that regulate blood pressure and Ca2++ metabolism

• produces an active form of vitamin D that promotes strong, healthy bones

erythropoietin

• releases as a response to low blood pressure

• travels to the bone marrow and stimulates the production of new blood cells

• produced by the peritubular cells of the kidney

metabolism of amino acids

• can be used for energy or broken apart to make fat

• requires the removal of the amine group (NH2), which gets converted into ammonium ion (NH4+)

  • toxic and highly water soluble

  • liver turns ammonia to urea, which is less toxic and less soluble

filtration occurs in the…

glomerulus → tubulues

reabsorption occurs in the…

tubules → peritubular capillary

secretion occurs in the…

peritubular capillary → tubules

excreted load

filtered load + secreted load - reabsorbed load

urinary excretion rate

glomerular filtration + tubular secretion - tubular reabsorption

glomerular filtration

• the only place in the system where the blood is actually “filtered”

• blood pressure is used to push plasma through capillary walls and into Bowman’s capsule (BC)

  • plasma moves from the capillaries into the capsule

glomerulus

• where filtration occurs

• the capillary of the nephron

• high hydrostatic pressure (50mmHg) relative to other capillary beds

• fenestrated endothelium

• surrounded by Bowman’s capsule (BC)

• fluid and solutes move from glomerulus to BC

glomerular filtration flow of blood

1. renal artery

2. afferent arteriole

3. glomerular capillaries

4. efferent arterioles

5. peritubular capillaries

6. renal vein

in order or a substance to enter tubules, it must pass the following (in this order)

1. fenestrated endothelium of glomerular capillary

2. basement membrane

3. podocyte: main determinant of what gets filtered

fenestrated endothelium

• large pores that allow fluids, solutes, and some proteins to pass through

• blood cannot pass though

basement membrane

• heparin sulfate: blocks protein filtration by charge

  • blocks negatively charged proteins (albumin)

• type IV collage and laminin: blocks protein filtration by size (albumin)

epithelial podocytes

• highly specialized cells are attached to the basement membrane by foot processes

• filtration slits or slit diaphragm in between foot processes

• main determinant of what gets filtered

what gets filtered

• water

• ions

• urea

• glucose

• amino acids

• phosphate

proximal tubule

• nutrients (salts, amino acids, vitamins) are moved out of the tubule through active transport

• water follows nutrients by osmosis

renal proximal tubular sodium reabsorption

• regulated by sodium transporters

  • sodium glucose transporter

  • sodium amino acid transporter

  • sodium hydrogen exchanger isoform 3

  • sodium phosphate cotransporter type 2 at apical/luminal membrane

  • sodium bicarbonate cotransporter

  • Na+/K+ ATPase in basolateral membrane

loop of henle

• tissue around it is salty, from active transport diffusion of sodium chloride

  • the salty conditions allow water to diffuse out

distal tubule

• active transport is used to move more nutrients out of concentrated urine

• some ions, drugs, and toxins are actively pumped into the tubule (tubule secretion)

collecting duct

• more water leaves the tube by osmosis, since the tube is surrounded by salty water

• some urea leaves by diffusion

sodium intake

• high dietary intake is associated with increased risk of hypertension, which is a risk factor for the development of cardiovascular disease

potassium intake

• increased dietary intake reduces stroke and blood pressure in people with hypertension

kidney’s role in regulating blood pressure

• pressure natriuresis (kidney-fluid mechanism): increases in arterial blood pressure are transmitted to the kidney as increased renal perfusion pressure, which leads to a rise in sodium and water excretion, returning blood pressure back to normal

natriuresis

• the process of sodium excretion in the urine through the action of the kidneys

• promoted by the ventricular and atrial natriuretic peptides as well as calcitonin, and inhibited by chemicals such as aldosterone

renin-angiotensin-aldosterone system

• plays a central role in maintaining the pressure-natriuresis relationship

• water and salt retention

  • effective circulating volume increases

  • perfusion of the juxtaglomerular apparatus increases

• inhibited by an increase in arterial blood pressure which in turn reduces the vasoconstrictor effects of angiotensin II on the afferent arterioles, and decreases solute resorption in the proximal and distal tubules

RAAS system pathway

1. decrease in renal perfusion of the juxtaglomerular apparatus stimulates the kidney to make renin

2. renin converts angiotensin into angiotensin I

3. angiotensin converting enzyme (ACE) in the lungs converts angiotensin I into angiotensin II

4. angiotensin II leads to water and salt retention, increasing circulating blood volume, and thus increases the renal perfusion of the juxtaglomerular apparatus

5. increased perfusion tells the kidneys to stop making renin

angiotensin II

• sympathetic activity

• stimulates vasoconstriction, increasing blood pressure

• stimulates tubular Na+ Cl- reabsorption and K+ excretion, leading to water retention

• secretion of aldosterone and ADH (vasopressin)

aldosterone

• acts on the distal convoluted tubules and the collecting ducts in the kidneys, enhancing the reabsorption of sodium ions from the filtrate back into the bloodstream, leading to increased water retention and increasing blood volume

• facilitates the excretion of potassium ions into the urine, which helps maintain appropriate levels of potassium in the bloodstream

antidiuretic hormone (ADH or vasopressin)

• part of a negative feedback system which regulates water in the body

• increases the permeability of the distal tubule and collecting duct by inserting aquaporin channels, allowing more water to be reabsorbed into the blood

• stimulated by the posterior pituitary

• water is retained and concentrated urine is produced

diuretics

• causes more urine to be produced by the kidneys

• alcohol and caffeine are examples

  • alcohol inhibits ADH release, while caffeine interferes with its activity

arterioles

• high in oxygen and nutrients

• smallest arteries (resistance arteries)

• diameter controlled by

  • local factors (intrinsic)

  • sympathetic division (extrinsic)

  • long-term factors (hormones)

capillaries

• site of exchange of oxygen/CO2, nutrients, water

• single layer of endothelial cells and the basement membrane (basal lamina) that forms beneath the endothelium

  • forms a lumen that is just large enough for red blood cells to pass through one at a time

  • movement of fluids and solutes form a blood vessel to the interstitial space

  • first step is producing lymph and filtrate (urine production)

continuous capillary

• most common, least permeable

• intercellular clefts and transcellular cytosis allows for exchange of molecules

• abundant in skin and muscle

sinusoidal/discontinuous capillary

• most permeable and least common

• big ‘holes’ in endothelial membranes

• big clefts between cells

• found in liver, spleen, and bone marrow especially

interstitial space

between the cell and the capillary

paracellular movement

• water and solutes move across capillaries via endothelial pores

  • tight junctions and adherens junction

transcellular movement

• water and solutes more across capillaries directly through the cell membrane via vesicles

positively charged molecules

are more permeable than negatively charged

• most plasma proteins carry negative charge (albumin)

small proteins

can diffuse through inter endothelial clefts or through fenestrate less than 1 nm in diameter

large macromolecules

can cross the capillary at a very low rate, through wide intercellular clefts, fenestrations, and gaps (paracellular)

• plasma proteins

transcytosis (transcellular) is the predominant way

• pass through the cell inside of vesicles

• not governed by laws of diffusion

in general, there is not much movement of these molecules across a capillary wall, which contributes to the capillary oncotic pressure (πc)

endothelial pores

• paracellular pathway

• the determinant of permeability

  • depends on the number of tight/adherens junction proteins (allow cells to stick together)

  • lots of junction proteins = decreased amount of pores/pore size = decreased diffusion = decreased permeability

  • mostly water and ions

vesicular transport

• transcellular pathway: through the cell membrane

  • water goes through aquaporin 1 (AQP1)

  • channels for ions to move down their concentration gradients (Na+, K+)

  • carriers (Na+/K+ ATPase)

  • any non polar substance can move directly through a cell membrane and does not need a carrier (O2 and CO2 gases)

• plasmalemmal vesicles transport and large polar molecules

transcapillary flux of solutes

• follows Ficks Law of diffusion

• diffusion is determined by permeability and concentration gradient

Ficks Law of diffusion

Js = Px (Cp-Ci)

Px = (Dx * A) / x

Js

net flux of a solute through the capillary membrane (moles/cm2)

Px

the ease with which a solute crosses the endothelium (cm/sec)

• depends on surface area, distance across endothelium, and solute permeability

Cp-Ci

concentration difference of the solute across the capillary wall (moles/liter)

apical

• facing the lumen → urine

• inside the cell

basolateral

• facing the interstitum → peritubular capillary

• outside the cell

what is filtration?

• the removal of solutes as a solution flows across a porous membrane

• solutes too large to pass through the pores are filtered out of the solution

• the driving force is hydrostatic pressure (blood pressure)

net hydrostatic pressure

Pc - Pi

capillary hydrostatic pressure (CHP)

• pressure exerted by blood against the wall of a capillary

  • the force that drives fluid out of the capillaries and into the tissues

• the same as capillary blood pressure

Pc

• capillary hydrostatic pressure

  • force pushing fluid out of the capillaries

  • average 35mmHg at arteriole end and 15 mmHg at venous end of capillary

Pi

• interstitial hydrostatic pressure

oncotic pressure (p) or colloid osmotic pressure

• the osmotic pressure generated by large molecules (especially proteins such as albumin) in a blood vessel’s plasma (blood/liquid)

  • since albumin is too big to diffuse across the membrane, water moves from a higher concentration of water to a lower concentration of water (where more of the albumin molecules are)

    • volume of the plasma side increases due to the movement of water

aortic arch and carotid sinus

where arterial baroreceptors are located

• measures blood pressure of blood

  • activated when blood pressure is high

  • decreases stroke volume and heart rate to decrease BP

plasma proteins that contribute to oncotic pressure

• gloulins

• fibrinogen

• albumin

net oncotic pressure

πc - πi

• πc = capillary plasma colloid osmotic pressure

  • pulling force plasma protein to keep fluid in vessel (25mmHg)

• πi = interstitial colloid osmotic pressure

  • pulls water out of capillary and into interstitium (0mmHg arteriole to 40mmHg venous)

starling’s equation: determination of membrane permeability

Jv = Kf [(net hydrostatic pressure) - σ(net oncotic pressure)]

• Jv = trans endothelial solvent filtration volume per second

• σ = correction factor

• the fraction of plasma and interstitial proteins which can pass across the endothelium

  • 0 = vessel completely permeable to protein

  • 1 = proteins can’t cross the endothelium (eg. brain)

filtration coefficient (Kf)

• the relative permeability of the membrane overall

  • normal renal Kf is 12.5ml/min/mmHg

  • depends on the amount of junctions (adherens, tight)

Jv > 0

filtration out of capillary

Jv = 0

no net movement

Jv < 0

absorption into capillary

effects of histamine on vasculature

• causes arteriole dilation and venous constriction, leading to more blood in capillaries

  • more blood enters from arteriole (decreased resistance) and less blood can leave (increased resistance on venous end)

• increases Pc and Kf (membrane becomes more permeable)

where fluid can move from the capillary to the interstitial space

1. re-enters the circulation at the venous end of the capillary (absorption)

2. or, enters the lymphatic system, which transports the fluid to the circulation again

   • the lymphatics drain the interstitial space of excess fluid

   • lymphatics allow removal of large particulate matter and proteins from the interstitial space

   • contains white blood cells

formation of lymph

1. blood pressure causes net filtration from capillaries. some of this fluid leaks

2. this leaked fluid is called interstitial fluid, which surrounds cells and consists of water, dissolved ions, waste, etc

3. interstitial fluid is collected by lymph capillaries, which have flap-like structures that open when the interstitial fluid pressure is higher than the pressure inside the lymphatic capillaries, allowing fluid to enter

4. the collected fluid, now referred to as lymph, moves through larger lymphatic vessels—these vessels have one-way valves that prevent the backward flow of lymph, ensuring it moves in the right direction

lymph nodes

1. filter and cleanse the lymph by removing debris, pathogens, and foreign substances.

2. lymphocytes, a type of white blood cell, are also present, contributing to the immune response.

internal pumping

• increased stretch of the lymphatic vessels (by lymph) causes the smooth muscle that lines them to contract (myogenic auto-regulation)

• lymphatic valves prevent back flow and keeps lymph from moving in one direction

external pumping

• skeletal muscle pump

• during exercise the rates of lymph flow can increase 10 to 30 times

• the diaphragm is a skeletal muscle important for lymph movement

where lymph empties back into the venous circulation

the subclavian veins