Test 2 (Tubular Transport: Basic Principles, Organic Solute Transport) Flashcards
“Logic” of Renal Handling of Substances
- Bulk filtration of all small molecules into Bowman’s Capsule
- Selective retention of useful materials by Tubular Reabsorption
- Unwanted material pass into urine
- Some transport processes are Physiologically regulated to CONTROL AMOUNTS of SUBSTANCES in Body Fluids
Renal Handling of Water, Sodium, Glucose, and Urea
1) Water:
a) Amount filtered per day:
- 180 g
b) Amount Excreted:
- 1.8 g
c) Percent Reabsorbed:
- 99%
2) Sodium:
a) Amount filtered per day:
- 630 g
b) Amount Excreted:
- 3.2 g
c) Percent Reabsorbed:
- 99.5%
3) Glucose:
a) Amount filtered per day:
- 180 g
b) Amount Excreted:
- 0 g
c) Percent Reabsorbed:
- 100%
4) Urea:
a) Amount filtered per day:
- 56 g
b) Amount Excreted:
- 28 g
c) Percent Reabsorbed:
- 50%
Structure of Tubular Epithelium
- Basement Membrane
- Basolateral Membrane
- Interstitial Fluid
- Tight Junction
- Luminal Membrane
Transcellular vs Paracellular Movement
Transcellular:
- Movement of Solute and Water THROUGH the CELL
Paracellular:
- Movement of Solute and Water THROUGH the TIGHT JUNCTION
Basic Mechanisms for Transcellular Solute Movement
PASSIVE (“Downhill”) TRANSPORT
PASSIVE (“Downhill”) TRANSPORT:
1) Simple Diffusion:
- “Down” electrochemical gradient via LIPID BILAYER or Aqueous Channels
2) Facilitated Diffusion:
- “Down” electrochemical gradient; SPECIFIC CARRIERS REQUIRED
Basic Mechanisms for Transcellular Solute Movement
ENERGY–DEPENDENT (“Uphill”) PROCESSES
ENERGY–DEPENDENT (“Uphill”) PROCESSES:
1) Primary Active Transport:
- AGAINST Electrochemical Gradient; ATP HYDROLYSIS provides Energy
2) Secondary Active Transport:
- “Downhill” movement of one substance provides ENERGY for “Uphill” movement of another substance
- Cotransport, Countertransport
3) Pinocytosis:
- Protein Reabsorption
Proximal Tubular Transport
- Proximal Tubule Reabsorbs most of FILTERED Water, Na+, K+, Cl-, Bicarbonate, Ca2+, Phosphate
- Normally, reabsorbs ALL the FILTERED Glucose, Amino Acids
- Several Organic Anions and Cations (Including Drugs, Dug Metabolites, Creatinine, Urate) are secreted in PROXIMAL TUBULE
TF/ Plasma Concentration Ratios Provide information on Tubular Handling of Substances
- What fraction of filtered water is reabsorbed in Proximal Tubule?
(HINT: Look at INULIN Concentration Ratio)
- Na+ Concentration DOESNT CHANGE- does this mean Na+ isn’t Reabsorbed???
- Concentration fo Urea and Cl- INCREASE Somewhat, are these compounds secreted by Proximal Tubule? What about PAH?
TF/ P Ration in Proximal Tubular Lumen: INULIN
TF/ P = 3!!!!!
TF/ P Ration in Proximal Tubular Lumen: GLUCOSE
TF/ P = 0!!!!!
TF/ P Ration in Proximal Tubular Lumen: PAH
TF/ P = 10!!!!
Proximal Tubular Na+ Reabsorption
- Provides driving force for Reabsorption of Water, other solutes
- Polarity of Epithelial Cell membranes facilitates net UNIDIRECTIONAL TRANSPORT
- Ultimately powers by Na+, K+, ATPase in Basolateral membrane
- Na+ Reabsorption usually coupled to Transport of/ Exchange for another solute
Sodium Reabsorption is linked to Transcellular Transport of other substances
LUMEN:
1) Na+ and Glucose (Same direction)
2) Na+ and H+ (Opposite)
3) Na+, K+, Cl- (Same Direction but move 2 Cl-)
INTERSTITIUM:
1) Na+ and K+ (Opposite)
- Na+, K+, ATPase
Water Reabsorption follows Na+ Reabsorption
- In Proximal Convoluted Tubule, BULK FLOW!!!!
Paracellular Reabsorption of Cl- and Urea in Early PCT
- Not ACTIVE process, but ultimately DEPENDENT on Na+ and Water Reabsorption
- As Na+ and Water are Reabsorbed, Cl- and Urea become more concentrated in Luminal Fluid
- Modest concentration Gradient between Lumen and Peritubular Interstitial provides driving force for PARACELLULAR REABSORPTION
TF/P Concentration Ratios
- Note modest INCREASE in UREA and CL- Concentrations in Tubular Lumen
Factors Promoting Fluid Movement into Peritubular Capillaries
1) HIGH PLASMA COLLOID OSMOTIC PRESSURE in the Peritubular Capillary Blood (Due to Filtration of Fluid in Glomerulus)
2) LOW HYDROSTATIC PRESSURE in these Capillaries
3) CONSEQUENCE: Almost as much Fluid is Reabsorbed as was initially Filtered into Bowman’s Capsule
Impact of Organic Nutrient Handling
- Large amount of Nutrients (Glucose, Amino Acids) filtered each day; must be RETAINED
a) Small molecules: free filtered
b) Completely reabsorbed by Proxima Tubule
c) Mo reabsorption in more Distal Segments
- Kidneys DONT regulate PLASMA CONCENTRATION of Glucose and Amino acids, Liver and Endocrine systems do!!!
Basic Mechanism of Tubular Reabsorption of Glucose and Amino Acids
- Secondary ACTIVE TRANSPORT; Transcellular only
- Uptake accrois Luminal Membrane:
a) Against Concentration Gradient
b) Coupled to Na+ entry down its Electrochemical Gradient
c) Ultimately dependent on Na+, K+, ATPase
- Exits Cells through BASOLATERAL MEMBRANE by FACILITATED DIFFUSION
Mechanisms of Glucose Reabsorption
Luminal Membrane:
1) Na-Glucose COTRANSPORT
Basolateral Membrane:
1) Facilitated Diffusion
Glucose reabsorption is Saturable
- Limited number of Na+, Glucose Cotransproters in Luminal Membrane
- If filtered amount (load) of Glucose (=GFR x Pglucose) EXCEEDS a CERTAIN RATE:
a) Capacity of Nephrons to Reabsorb all the Filtered Glucose is exceeded
b) Glucose appears in the Urine (GLUCOSURIA)
- Identify a disease in which saturation occurs
- Same principles apply to Amino Acid Transport
Glucose Reabsorption is Saturable
- TmG= Tubular Glucose Maximum
Ex: Maximum rate of Glucose Reabsorption by all the Nephrons COMBINED
Questions for Discussion
- Would the Filtered Load of Glucose change if GFR INCREASED by Plasma Glucose Concentration remained Constant? How would this affect the Threshold Value?
- Would an inhibitor of the Renal Tubular Na+, K+ ATPase affect Reabsorption of Glucose? Why?
- Urine Output increases in Diabetes. Why?
- Why would a Diabetic patient by thirsty?
Consequences of Osmotic Diuretics
- INCREASED Water Excretion
- INCREASED Sodium Excretion (Why?)
Secretion of Organic Anions (PAH, Bile Salts, Uric Acid, Creatinine, etc) in PCT
- TERTIARY Active Transport
- Also drugs such as Penicillin, Salicylates, some Antiviral Drugs
PAH Secretion
- PAH Secretion is Saturable so that the Secretion can reach its threshold and therefore the Excreted PAH will not increase with such a steep slope
Secretion of Organic Cations in PCT
- Catecholamines, Acetylcholine, Dopamine
Passive Diffusion of Organic Acids and Bases
- Organic anions and Cations are ionized forms of Weak Acids and Bases, respectively
- CHARGED FORMS: Highly Polar compounds CANNOT READILY DIFFUSE through Lipid Bilayer
- UNCHARGED MOLECULES: Less polar, more lipid-soluble and therefore MEMBRANE-PERMEABLE
Biochemistry of Weak Acids and Bases
- Weak ACIDS are Neutral when PROTONATED:
A- + H+ = HA - Weak BASES are Neutral when DEPROTONATED:
B + H+ = BH+ - ACIDS SOLUTIONS generate Neutral forms of WEAK ACIDS
- BASIC SOLUTIONS generate Neural forms of WEAK BASES
Tubular Handling of Organic Acids and Bases is affected by pH of Luminal Fluid
- H+ in the Tubular Lumen FAVORS REABSORPTION of Organic Acids, but TRAPS Organic Bases in the Lumen
Effects of Luminal pH on Tubular handling of Organic Acids and Bases
- LUMINAL ACIDIFICATION favors REABSORPTION of Organic Acids, EXCRETION of BASES
- Many drugs are Weak Acids or Bases
- If your patient Overdoses on ASPIRIN (Acetylsalicylic Acid, an Organic Acid), how can you promote Urinary Excretion of Aspirin to help eliminate it from his body???
~~~~~MAKE URINE ALKALINE!!!!!
Summary: Basic Tubular Processes
- Large amounts of Small Molecules filtered each day; most Reabsorbed, especially in PROXIMAL TUBULE
- Two routes: TRANSCELLULAR, PARACELLULAR
- Na+ Reabsorption provides driving force for Solute and Water Transport in PROXIMAL TUBULE
- Reabsorbed materials enter PERITUBULAR CAPILLARIES by BULK FLOW!!!!!!!
- Osmotic Diuretics INCREASE H2O, Na+ EXCRETION
Summary: Proximal Tubular Handling of Organic Compounds
- Organic Nutrients: Reabsorbed by SECONDARY ACTIVE TRANSPORT, linked to Na+ Reabsorption
- Glucose Reabsorption is Saturable; Glycosuria occurs when Filtered Load exceeds Reabsorptive Capacity of PROXIMAL TUBULAR EPITHELIUM
- Organic anions, Cations SECRETED by Tertiary Active Transport
- H+ secretions FAVORS REABSORPTION of Organic ACIDS, EXCRETION of Organic BASES
