Renal System

Functions of the kidney

• removal of metabolic waste and foreign chemicals through urine excretion

• regulates water and ion balance

• acid-base balance

• gluconeogenesis

• production of hormones/enzymes

Hormones that kidney secretes

EPO, 25-(OH)2D, renin

Macro structure of urinary system

kidneys→ureters→bladder→urethra

Ureter function

urine transport

Bladder function

urine storage

Urethra function

urine excretion

Macro structure of kidney

• renal cortex

• renal medulla

• renal pelvis

• ureter beginning

Nephron

structural and functional unit of the kidney

Two component of the nephron

renal corpuscle and renal tubule

Structure of nephron

1. glomerulus

2. proximal convoluted tubule

3. loop of Henle

4. distal convoluted tubule

5. cortical collecting duct

6. medullary collecting duct

Blood flow to and from nephron

• blood brought to glomerulus through afferent arteriole

• blood brought away from glomerulus through efferent arteriole

• peritubular capillaries surround loop of henle

Glomerular filter

• 3 ply filter

  • leaky capillary wall fenestrations

  • basement membrane

  • filter slits between podocytes

Makup of basement membrane

full of proteins and anions

Mesangial cells

cell type contained in glomerulus. smooth-muscle like cells that help regulate blood flow in glomerulus via contraction. Also engulf macromolecules that get hung up during filtration

Two type of nephron

• juxtamedullary nephrons

• cortical nephrons

Juxtamedullary nephrons

• located mostly in the medulla

• have long loops of Henle

• concentrate urine

Cortical nephrons

• located mostly in the cortex

• short loop of Henle

3 functions of the kidney

1. glomerular filtration

2. tubular secretion

3. tubular reabsorption

Glomerular filtration

move material from blood to glomerulus

Tubular secretion

move material from blood to tubule directly

Tubular reabsorption

move material from tubule back to peritubular capillaries

What drives glomerular filtration?

Starling forces

Permeability of glomerular capillaries to water and solute

incredibly permeable

glomerular pressure compared to systemic blood pressure

Much higher than would normally be found in capillaries. This is because blood is carried to and from by arterioles

Surface area of glomerular capillaries

Huge surface area→good for efficient filtration

What CANNOT cross glomerular filter

large anions, proteins RBCs, anything bound to proteins

Purpose of inability of proteins to cross glomerular filter

Must maintain plasma oncotic pressure!

Hydrostatic pressure of glomerular capillaries vs bowman’s capsule

Much higher in glomerular capillaries

Oncotic pressure in glomerular capillaries vs Bowman’s capsule

Oncotic pressure in bowman’s capsule virtually nonexistent

Effect of constricting afferent arteriole on glomerular filtration

decreases hydrostatic pressure and thus decreases filtration

Effect of constricting efferent arteriole on glomerular filtration

backs up pressure, which increases filtration

Effect of dilating afferent arteriole on glomerular filtration

increases hydrostatic pressure, which increases filtration

Effect of dilating efferent arteriole on glomerular filtration

loosens pressure, causing hydrostatic pressure to drop and thus decrease filtration

Where does tubular reabsorption begin?

begins as soon as filtrate enters tubule

Main type of transport that tubular reabsorption occurs by

Usually through transepithelial transport (either active or passive). Few paracellular transport can occur

Is tubular reabsorption active or passive?

Can be either!

Materials that are reabsorbed

water, glucose, urea, sodium, amino acids, vitamins, important ions

Type of transport that tubular secretion usually occurs by

transepithelial transport. Not much paracellular transport

Is tubular secretion active or passive?

Can be either!

Glucose reabsorption graph based on different BGLs

• usually all glucose is reabsorbed

• however, if BGL gets too high, kidney stops glucose reabsorption and starts excretion

Why does glucose reabsorption stop at a certain point?

Glucose transporters are saturated

Calculating glucose lost

filter load—reabsorption

Most abundant cation in filtrates

sodium!

Importance of sodium

• helps do water balance

• movement of other substaces depends on sodium moving down its gradient

Type of transport involved in sodium reabsorption

Almost always active

Importance of tubular secretion

• remove drug and drug metabolites from blood

• eliminate urea/uric acid

• remove excess potassium

• regulate pH

Metabolic role of kidneys

• can do gluconeogenesis to replenish BGL during fasting

• break down organic compounds in preparation for secretion

How do you regulate reabsorption and secretion?

• regulate amount of transport proteins

• based on autocrine, paracrine, and hormonal signals

Where does majority of reabsorption occur?

PCT and loop of Henle

How is sodium reabsorbed in PCT?

1. Sodium transferred to epithelial cells via cotransport and antitransport

2. Sodium returned to interstitial fluid of capillaries via sodium potassium ATPase on basolateral membrane

   1. Potassium leak channels on the basolateral membrane allow potassium to flow down concentration gradient, allows Na/K ATPase to keep functioning

How is sodium reabsorbed in DCT?

1. moves down gradient using sodium channels from tubule to epithelial cells

2. moves into interstitial fluid of capillaries via Na/K ATPase

   1. K is secreted through K leak channels located on the luminal membrane, allowing Na/K ATPase to keep functioning

Reabsorption of water

Water follows sodium! This is because as sodium decreases, osmolarity decreases and water flows down the osmolarity gradient

Type of transporter used by water

aquaporin

Renal clearance

quantitative metric of filtration function that describes the volume of plasma cleared of a substance in one minute

Renal clearance equation

C=UV/P

• C→clearance

• U→concentration of substance in urine

• V→flow rate

• P→concentration of substance in plasma

What type of substance should you use to measure renal clearance?

Use a substance that is ONLY filtered (not reabsorbed or secreted)

What is urine composed of?

Filtrate that isn’t reabsorbed

How is micturition reflex triggered?

Via the stretch of smooth muscles in bladder

Types of nerves that innervate bladder

• parasympathetic

• sympathetic

• somatic

Three muscles of bladder

• detrusor

• internal sphincter

• external sphincter

Nervous system input to detrusor muscle during bladder filling

Parasympathetic innervation of detrusor muscle is inhibited

Nervous system input to internal sphincter during bladder filling

Sympathetic input to internal sphincter is stimulated

Nervous system input to external sphincter during bladder filling

Somatic input of external sphincter is stimulated

Nervous system input to detrusor muscle during bladder emptying

Parasympathetic innervation of detrusor muscle is promoted

Nervous system input to internal sphincter during bladder emptying

Sympathetic input to internal sphincter is inhibited

Nervous system input to external sphincter during bladder emptying

Somatic input of external sphincter is inhibited

Total daily intake and loss of water

Intake: about 3 L

Loss: about 3 L

• they’re equal!

Sources of fluid loss

• urine (major)

• insensible loss in skin and lungs

• sweat and feces

What type of process is sodium reabsorption: passive or active?

Active

Places sodium is reabsorbed

All tubular segments (70% in PCT) except in descending loop of Henle and the medullary collecting duct

How does water reabsorption occur?

Through diffusion thanks to aquaporins. Dependent on sodium

Places of water reabsorption

Everywhere except in the ascending loop of henle and the cortical+medullary collecting ducts→unless hormones act upon collecting

Hormone influence on cortical collecting duct

• Aldosterone acts on cortical collecting duct to increase sodium and water reabsorption

• Vasopressin acts to increase ONLY water reabsorption

• PTH acts to increase Ca2+ reabsorption

How does aldosterone increase sodium reabsorption in the cortical collecting duct?

• upregulated sodium channels and sodium potassium ATPase

• induces obligatory potassium secretion by upregulating K+ channels in luminal membrane

Water absoprtion in the cortical collecting duct under the influence of aldosterone

• water follows sodium through aquaporins

What happens when sodium is reabsorbed but not water?

Changes in osmolarity, which induces water reabsorption

Vasopressin (ADH) effect

• increases aquaporin proteins in luminal membrane of medullary collecting duct

• increases urea transporters

• directly acts on arterioles to increase vasoconstriction and therefore TPR

Aquaporin regulation

1. vasopressin (ADH) binds to receptor on basolateral membrane of collecting duct epithelial cells

2. adenylyl cyclase activated through GPCR mechanism, causing a rise in cAMP and subsequent PKA activation

3. PKA phosphorylates AQP2, which is contained within vesicles

4. Phosphorylation causes vesicles to fuse with luminal membrane

5. Aquaporins added to luminal membrane

Are other aquaporins always present in the basolateral membrane in collecting duct?

Yes!

Importance of urea

sets up osmotic gradient for H2O reabsorption in medullary collecting duct. Without urea, you can’t achieve a hyperosmolar environment that favors reabsorption

Glomerular filtration rate

volume of filtrate formed each minute

What affects glomerular filtration rate?

• volume of surface area available

• filtration membrane permeability (can’t regulate this though)

• net filtration pressure/starling forces

• blood pressure/blood flow

Relationship between glomerular filtration rate and net filtration pressure

directly proportional

Cascade of sodium loss effects on GFR and blood pressure

Decreased sodium leads to decreased MAP, which stimulates increased renal sympathetic output, leading renal arteriolar constriction and decreased GFR, which decreases the amount of sodium and water excreted

Where is aldosterone synthesized?

zona glomerulosa of adrenal cortex

Renin angiotensin system

angiotensinogen→angiotensin I→angiotensin II→aldosterone→Na+ and H2O retention; vasoconstriction→increased blood pressure

Production of angiotensinogen

Produced in the liver all the time

Activation of angiotensinogen into angiotensin I

Converted into angiotensin I by renin ONLY when blood pressure fall

Conversion of angiotensin I into angiotensin II

Angiotensin converting enzyme in the lungs

Effects of angiotensin II

• binds zona glomerulosa cells in adrenal cortex

• directly increases vasoconstriction

3 components of the juxtaglomerular apparatus

• afferent arteriole

• macula densa in the DCT

• juxtaglomerular cells wrapped around afferent arteriole

Purpose of JG apparatus

control secretion of renin by sensing changes in blood pressure

What does the macula densa sense?

has chemoreceptors that sense NaCl content of filtrate

What do the JG cells sense?

mechanoreceptors that sense arteriolar wall stretch, and therefore BP. Also the cells that directly secrete renin

Three stimuli that stimulate renin secretion from JG cells

• arterial stretch

• Na content reported from macula densa

• sympathetic innervation of JG cells

Effects of decreased plasma volume on renin secretion diagram

All of this leads to increased secretion of renin by JG cells which decreases sodium and water loss and promotes their reabsorption

Where is atrial natriuretic peptide (ANP) produced?

cardiac atrial cells

When is ANP produced?

When atria are more distended→greater plasma volume

What kind of signal is ANP and what is the consequence on signaling?

Water soluble hormone; therefore, it must act through a cell surface receptor

ANP and sodium excretion diagram

ANP secretion leads to renal afferent arteriole dilation and efferent arteriole constriction, increasing GFR and therefore sodium excretion