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GLOMERULUS (. (. (. (.. (. (. (. (. (. (. (. (. (. (. (. (. (. (Thick…
GLOMERULUS
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Na+/H+ antiporter
- H+ into lumen to transport
bicarbonate out of lumen
- Na+ reabsorbed from lumen
Na+/K+ ATPase Pump
- pumps Na+ out to interstitium and K+ into the cell
- creates low Na+ gradient inside the tubule cells
- secondary active transport
--> provides energy
(as gradient) to bring Na+ in from the lumen
Essential solutes Reabsorbed:
- Na+ (65%)
- glucose (ALL)
- HCO3-
- amino acids
- Urea (50% reabsorbed)
Some H2O reabsorbed passively
- following the solutes
- mainly b/c high oncotic pressure in the cappilaries
(no protein filtered at the Glom.)
CARBONIC ANHYDRASE INHIBITORS
- ex: Acetazolamide
- not used as diuretics
- used to alkalize the urine, often with drugs that cause urolithiasis = forming urinary stones due to high acidity in the urine
- prevent re-absorption of NaHCO3 and
-->alkalize the urine
- also used for closed and open glaucoma
--> same HCO3- reabsorption in the eye as in PCT
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OSMOTIC DIURETICS
- ex: Mannitol
- work on all parts of nephron permeable to water
- PCT, descending LOH, CD (when ADH present)
- rapid reduction in intraocular + intracranial pressure
Main Goal of PCT cells
- reabsorb sodium
--> apical side - antiporter with H+
--> no net movement of H+ (gets used up by CA enzyme)
- reabsorb bicarbonate
--> needs CA = carbonic anhydrase in both the lumen and the PCT cells
--> H20 and CO2 can passively cross the apical membrane
--> both sodium and bicarb cross basolateral side by Na+/HCO3- symporter to enter blood
*PCT Major Functions
- Most Na+ AND K+ = 65% is reabsorbed at the PCT
- ALMOST ALL water = 60% absorbed in the PCT
--> this is done passively as the water follows the Na+
--> reason why they are are so close (65% Na+ and 60% H2O)
- ALL Glucose = 100% is absorbed at the PCT
PCT Glutamine --> Ammonia Buffer System
- ""GLUED to your BUNs" = Kidney functions
--> Glutamine restores Bicarb production at PCT
--> BUN = reabsorbs urea to concentrate you urine
- Glutamine --> glutamate --> HCO3- bicarb synthesis
- Histamine in PCT is the main provider for the bicarb in the
--> renal bicarb compensation for metabolic acidosis
- important for any kinds of ischemia (acute ischemic colitis)
--> that causes lactic acidosis (= raised ion gap)
--> MUDPILES
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*Osmolarity and Water Absorption in the Nephron
- ALMOST ALL water = 65% absorbed in the PCT
--> this is done passively as the water follows the Na+
--> reason why they are are so close (65% Na+ and 65% H2O)
- 20% of water reabsorbed at the DLH = descending loop of H
--> this is done by concentrating the urine actively
--> when ADH increases AQP - 2 at the DCT, Urea is also reabsorbed with it to concentrate the urine and absorb more water at the DLH
*Water Absorption in the Nephron
- ALMOST ALL water = 65% absorbed in the PCT
--> this is done passively as the water follows the Na+
--> reason why they are are so close (65% Na+ and 65% H2O)
- 20% of water reabsorbed at the DLH = descending loop of H
--> this is done by concentrating the urine actively
--> when ADH increases AQP - 2 at the DCT, Urea is also reabsorbed with it to concentrate the urine and absorb more water at the DLH
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*Osmolarity Absorption in the Nephron
- NORMAL Osmolarity in the plasma = 300 mOs
--> thus the PCT starts with Omsolarity = 300 mOS
--> ISOTONIC = 300 mOS
- with ADH present - max Osmolarity = 1200 mOS
--> bottom of loop
--> end of CD (where the ADH reabsorbs all the water)
- HYPOTONIC urine =100
--> at the DCT
--> think that LOOP and THIAZIDES work at the ascending limp and DCT
--> BUT no water can follow the NaCl like in the PCT
--> thus the water stays and the salt leaves
--> MOST dilute urine in DCT = 100
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SGLT2 Na+/glucose (reabsorb) transporter
- high capacity
- low affinity
- first 1/3 of PCT
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HCO3- = BICARBONATE
- ALL filtered at the Glomerulus
- almost ALL reabsorbed at the PCT
- requires H+ to be transported out of lumen
H+ + HCO3- --> H2CO3
- CARBONIC ANHYDRASE catalyzes both directions of H2CO3 --> H2O + CO2
- H2O + CO2 can then diffuse across the tubule cells
- Bicarbonate Regeneration:
Glutamine released from liver, muscles, GIT
Glutamine --> 2NH4+ + 2HCO3-
(H+ captured in Ammonium, then excreted)
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Urea Reabsorption
Urea Reabsorption
Notes:
- note that Urea absorption always follows water with ADH
- Urea is used to concentrate urine
- think that when water leaves the duct, then the duct is high urea concentration and needs to leave to go to the interstitium of the kidney
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Urea Trapping
- ADH primarily absorbs water at the CD
- secondary action of ADH is to increase UTI1
--> increase urea absorption
--> this creates the gradient needed at the Loop of H for concentrating the urine
--> think of it as since you are reabsorbing all the water, you are saving the Urea in the Loop for later when you need to concentrate that same water
NSAIDS
- block PDA = Prostaglandins DILATE the Aferrent
- reduce RBF tot he kidney
- reduce Loop diuretics and other diuretics action
--> can cause edema in people on diuretics
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*LOOP DIURETICS
- remember "furious BUM beside me on the Loop-D-Loop"
- ex: furosemide = LASIX, bumetanide
- oral/I.V.
- inhibit Na+/K+/2Cl- cotransporter
- LOOPS lose Ca2++, Thiazides SIDE with Ca++
--> they both LOSE K+ and H+ though from reactive RAAS
--> aldosterone wastes K+ (principle cells) and H+ (ICCs) at the DCT and CD
- POTENT diuretics (excrete 15-20% Na+)
Na+, Cl-, H20 and K+, Ca++, Mg++
--> used 1st line in CHF
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(loops)
Prostaglandins
- PDA = Prostaglandins DILATE the Aferrent
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PDA ACE Regulation of GFR
- PDA = prostaglandins dilate afferent
- ACE = Angiotensin 2 constricts the efferent
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(1) (DCT) Macula Densa Cells
--> chemoreceptors/osmoreceptors
sense low Na+/Cl- levels
(2) Extraglomerular Mesangial Cells
--> help send message from the DCT (Mac. Densa) to the Jixta. cells
--> "extra" = outside/not directly beside Glomerulus
--> "Mesangial" = messengers between Macula Densa and Juxtaglomerular cells
(3) Juxtaglomerular/Granular Cells (PCT)
--> mechanoreceptors
sense low blood pressure
--> also recieve signal of
low Na+/Cl- from DCT
--> release renin (angiotensin pathway)
--> aldosterone, ADH, reabsorption effects
Notes:(1) Nephrons are of 2 types:
- Cortical Nephrons
--> 85% of nephrons
--> short Loop of Henle
- Juxtamedullary Nephrons
--> produce concentrated urine
--> LONG Loop of Henle
(2) GFR
- average GFR=120 in range of 90-140 (ml/min)
- 120/600 = 20% of blood filtered at Glomerulus
- blood plasma is filtered approx. 60 times/day
(3) Freely-filtered substances
- DOES NOT mean all of the substance is filtered
- means that the filtered plasma contains
same concentration as in the unfiltered plasma
(4) Juxtaglomerular Complex
- Communication between the DCT and the afferent arteriole
--> afferent arteriole: best measure of bp in the body entering kidney
--> DCT: best measure of solute filtration after most reabsorption has already occured
- In actuality, the renal corpiscle should face the distal tubule
to receive signals from the DCT Macula Densa Cells
(5) 3 Layers of Glomerular Filtration
- Layer 1: vascular endothelial layer
--> single squamous cell layer
--> fenestrated with microscopic pores (~70 nm diameter)
- Layer 2: basement membrane
--> non-cellular [Collagen and Glycoproteins (fibronectin and laminin)]
--> (-) charge on Glycoproteins repels (-) charged proteins (albumin)
- Layer 3: visceral epithelial layer of B. capsule = podocytes (fingers)
--> "podo" means foot --> foot cells (~25-40 nm diameter)
--> slit diaphragms between the podocytes have (~8 nm diameter) pores
(6) Glomerular Filtration
- Passed through filter:: Water, Electrolytes, Glucose, Amino acids,
Fatty acids, Vitamins, Urea, Uric acid, Creatinine
--> (+) molecules > (-) molecules
- Turned Back:: RBCs, Plasma proteins, Large anions,
Protein bound minerals and hormones
--> Albumin: small enough (6 nm diameter), but (-) charge
(7) Minimal Change Nephropathy
- lose (-) charge on the basement membrane layer
(even before histology changes noticed)
- allows smaller (-) charged proteins like albumin/transferrin to pass filtration
- leads to proteins in the urine --> proteinuria or albuminuria
(8) (PCT) PROXIMAL CONVOLUTED TUBULE
- Main site of Reabsorption
- Large surface area: lots of vili
- Transport abilities: many vesicles to transport,
many mitochondria for ATP to transport
- Na+ moves into the cell and down its electrochemical gradient coupled to:
(glucose, amino acid, phosphate, lactate, or citrate), which move into the cell against their electrochemical gradients
(9) LOOP OF HENLE
- Thin limb
--> thin squamous cells : osmosis of water
- (TAL) Thick Ascending Limb
--> many mitochondria and vesicles for transport of ions
(10) (DCT) DISTAL CONVOLUTED TUBULE
- Main site of Secretion into Tubule
- Cuboidal cells without microvilli secrete contents
Descending
Vasa
Recta
- high resistance
- low blood flow to
maintain
hyperosmotic medulla
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Notes (continued):(11) COLLECTING DUCT
- Main site of Reabsorption
(12) O2 Consumption Dependent on Blood Flow
- In all other organs, blood flow is dependent on O2 consumption (ex: muscles)
- In kidneys, same correlation, but opposite causal effect
- O2 consumption dependent on the Na+ reabsorption and H+ATPase pumps,
which is determined by the blood flow to the kidney
(13) Blood Flow in Kidney
- Cortex: gets 90% of blood flow to kidney
- need low blood flow to the medulla to maintain hyperosmolarity
(otherwise blood would reabsorb the solutes from interstitium)
- allows juxtamedullary nephrons to produce highly concentrated urine
(14) Capillary Beds in the Kidney
- Systemic Capillary Beds:
--> filtration at the arterioles
--> reabsorption at the venules
- Peritubular Capillary Beds:
--> reabsorption at the arterioles
--> filtration at the venules
- Kidney's 2 Capillary Beds in Series:
--> major filtration at Glomerulus capillary bed
--> major reabsorption at peritubular capillary beds
(15) Pressure Control in the Kidney
- Afferent Arteriole Constriction:
--> Glomerulus pressure decreases
--> Peritubular pressure also decreases
--> Both afferent/efferent constriction decrease RPF
- Efferent Arteriole Constriction:
--> Glomerulus pressure increases
--> Peritubular pressure decreases
--> Both afferent/efferent constriction decrease RPF
(16) Innervation of the Kidney
- NO Parasympathetic innervation
- Sympathetic innervation:
--> Main effect is to increase Blood Pressure
--> Juxtaglomerular/Granular Cells: causes renin release
--> All other parts of Nephron: causes Na+ reabsorption
(17) Autoregulation of the Kidney
- intrinsic autoregulation:
--> occurs when: 80 < MAP < 180
--> done by constriction/resistance in the afferent and efferent arterioles
--> renin/angiotensin system
--> angiotensin 2 only causes constriction in the EFFERENT ARTERIOLE
--> prostaglandins (in both), but mainly dilation in the AFFERENT ARTERIOLE
- Extrinsic autoregulation:
--> occurs when: MAP < 80
--> sympathetic hormones override the intrinsic controls
--> primarily cause vasoconstriction in the AFFERENT ARTRIOLES
(18) Ion Exchanegs
- K+ moves in opposite directions as H+/Na+
- Paracellular Pathways:
--> only positive ions (besides H+):
Mg2+, Ca2+, Na+, K+
- Na+ always done by Active Transport
THICK
ASCENDING
LIMB
(of HENLE)
Pharmacology Notes:(1) Probenecid
- increases the excretion of uric acid
- blocks tubular excretion of penicillins
- increases serum levels of both furosemide (loop diuretic) and Heparin
Notes (continued 2):(19) 3 Layers of Tubular Transport
- luminal membrane of renal tubule
= apical membrane
- basolateral membrane of renal tubule
- peritubular capillary endothelium
(20) Reabsorption
- Most substances which are reabsorbed are 98-100% reclaimed. Notable
- exceptions are potassium (86%, variable) and urea (50%, variable).
(20) Sodium Reabsorption
- PCT
--> H+/Na+ antiporter
--> Na+/Cl- through paracellular transport
--> 65-70% of Na+ reabsorbed
- TAL
--> Na+/2Cl-/K+ symporter
--> 25% of Na+ reabsorbed
- DCT
--> Na+/Cl- symporter
--> 5% of Na+ reabsorbed
LATE PCT
- +4 mV charge
- high [Na+]
- 100% of glucose reabsorbed
- 65% of Na+ reabsorbed
- 65% of K+ reabsorbed
EARLY PCT
- -4 mV charge
- high [Na+]
- high [glucose]
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- SNS is the main factor that stimulate the release of Renin from Glomerular afferent granular cells
--> renin starts the RAAS system
--> Beta 1 receptors causes renin release
- renin also released due to DCT Mac Dens --> Juxta-messangial cells sensing low Na+ and low ECV
- Angiotensin 2 mainly constricts the efferent arteriole, although it does both
--> increases the GFR
- Angiotensin 2 also stimulates Aldosterone release
- aldosterone acts on the DCT and collecting ducts to
--> reabsorbs Na+
--> excretes K+ and H+
- ADH ALWAYS follows Aldosterone release (main factor)
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- works agianst ADH and the RAAS system
- right atrium of heart mechanoreceptors sense high BP
--> release ANP = atrial naturetic peptide
- 2 main goals of ANP mediated through the kidney
--> increase Na+ excretion
--> decrease Aldosterone
- decrease Na+ excretion
--> dilate afferent and constrict efferent to increase GFR and filter more Na+
--> decrease sodium reabsorption
- decrease aldosterone
--> decrease renal renin release
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