Renal PhysiologyTransport of solutes Dr. Sara Reza Quaid-e-Azam Medical College
Functions of the Kidney:Maintaining balance • Regulation of body fluid volume and osmolality • Regulation of electrolyte balance • Regulation of acid-base balance • Excretion of waste products (urea, ammonia, drugs, toxins) • Production and secretion of hormones • Regulation of blood pressure
The Kidney and the Nephron A. Renal Vein B. Renal Artery C. Ureter D. Medulla E. Renal Pelvis F. Cortex 1. Ascending loop of Henle 2. Descending loop of Henle 3. Peritubular capillaries 4. Proximal tubule 5. Glomerulus 6. Distal tubule
Overview of nephron functionFrom http://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookEXCRET.html
Membrane Transport • Passive diffusion Facilitated diffusion Osmosis • Active transport Primary active transport Secondary active transport Co-transport Counter transport
Passive Diffusion • When two aqueous compartments containing unequal concentrations of a soluble compound or ions are separated by a permeable membrane the solute moves by simple diffusion from the region of higher concentration, through the membrane, to the region of lower concentration, until the two compartments have equal solute concentration.
The diffusion velocity of a pure phospholipid membrane will depend on:• concentration gradient,• hydrophobicity,• size,• charge, if the molecule has a net charge
Facilitated Diffusion • Facilitated diffusion of ions takes place through proteins, or assemblies of proteins, embedded in the plasma membrane. These transmembrane proteins form a water-filled channel through which the ion can pass down its concentration gradient
• Proteins act as carriers or pores permit flux of substances that cannot diffuse directly through the membrane.• Movement is still passive (like diffusion), from high concentration to low.• Occurs across cell membranes only.• Related substances can compete for the same carrier or pore.• Maximum rate of transport (fully saturated) is called Tm, the transport maximum.
Osmosis • Diffusion of water down its concentration gradient is called osmosis.
Active Transport • When cell membrane moves molecules or ions uphill against concentration gradients or uphill against an electrical or pressure gradient, requiring energy, the process is called Active transport. • Types 1.Primary active transport 2.Secondary active transport
Primary active transport • Energy is derived directly from ATP • Best example is sodium potassium pump • Sodium potassium pump • Pumps Na ion outside and at the same time pumps K ion inside the cell to maintain Na K concentration across the cell membrane
• The carrier protein of Na-k pump -has three receptor sites for binding Na ions that protrude inside the cell -has two receptor sites for K ions on the outside -inside portion also has ATPase activity• When two K ion bind on outside of carrier protein and the Na ion on inside, the ATPase function becomes activated• Cleaves ATP• Liberate energy that cause conformational change in carrier molecule• Extruding three Na to outside and two K to inside.
Secondary active transport • Indirect active transport uses the downhill flow of an ion to pump some other molecule or ion against its gradient. The driving ion is usually sodium (Na+) with its gradient established by the Na+/K+ ATPase. • Types • co-transport • counter transport
Cotransport (Symport) • When Na ions are transported out of the cells by primary active transport a large concentration gradient of Na develops • This represent store house of energy because excess Na always attempt to diffuse inside cell • Under appropriate conditions the diffusion energy of Na can pull other substance along with Na through cell membrane • This phenomenon is called co transport • E.g. Na co transport of glucose
Counter Transport (Antiport) • Na ions again attempt to diffuse to interior of cells because of their concentration gradient • This time the substances must be transported to the outside • Once both have bound a conformational change occurs, energy is released by the Na ions moving to interior causes other substance to move to exterior • E.g. Na counter transport of Ca and H
Proximal convoluted tubule• Role: Initial adjustment of tubular fluid by reabsorption (main mechanism) and by secretion Reabsorption: Transport from tubular lumen to peritubular capillary blood Secretion: Transport from peritubular capillary blood into the tubular lumen
• Substances actively reabsorbed (mainly transcellular) Sodium ion about 70% (60-80%, including passive component) Chloride ion about 70% (60-80%, including passive component) Glucose complete Amino acids complete Inorganic phosphate complete Plasma proteins complete (only small amount filtered)
• Passive Reabsorption: due to concentrating effect of active reabsorption followed by water reabsorption plus solvent drag Sodium ion Chloride ion Bicarbonate ion variable (depends in part on H+ secretion) Potassium ion most or all Urea about 40% (because of low permeability) Water about 70% (60-80%) (due to osmotic effect of particle reabsorption)
Mechanism:• Active particle reabsorption (particularly Na+) creates a small osmotic gradient between the luminal fluid and the spaces between tubule cells on the interstitial surface.• The osmotic gradient causes water to be reabsorbed because the proximal tubule is very permeable to water.• The water reabsorption concentrates the remaining dissolved substances (including Na+), and, if they are readily permeable, the resulting concentration gradient leads to their reabsorption at about the same rate as water.
Note: The above mechanism maintains proximal tubule fluid approximately iso-osmotic with plasmaNote: About two-thirds of the water and filtered particles are reabsorbed in theproximal tubule. If the GFR is reduced, reabsorption is reduced in proprotion; ifGFR increases, reabsorption increases in proportion. This is termedGlomerular-Tubular Balance.
• Active Secretion 1. Mechanism: cotransport with Na+ ion reabsorption 2. Substances secreted, e.g. Exogenous Para-aminohippurate (PAH) Iodinated dyes (e.g., Diodrast) Certain pharmacological agents (e.g. penicillin, note effect of probenecid) Endogenous Hydrogen ion (Na+ antiport)
• No Transport 1. Not actively transported and tubule impermeable to diffusion Inulin (exogenous indicator) Creatinine (endogenous protein metabolism product)
Apical Transporters FunctionNa/glucose CT Na uptake, glucose uptakeNa/Pi CT Na uptake, Pi uptakeNa amino acid CT Na uptake, amino acid uptakeNa/lactate CT Na uptake, lactate uptakeNa/H exchanner Na uptake, H extrusionCl/base exchanger Cl uptake
Loop of Henle • Concentrates and dilutes urine • Descending limb is permeable only to water • Ascending limb is impermeable to water and acts as an active NaCl pump • 30% of the filtered sodium is reabsorbed using a luminal Na-K-2Cl- cotransport mechanism • Furosemide inhibits the Na-K-2Cl cotransporter and leads to a massive natriuresis and loss of potassium, calcium and magnesium.
Apical transporter FunctionNa, 2 Cl, K CT Na uptake, Cl uptake, K uptakeNa/H exchanger Na uptake, H extrusionK channels K extrusion (recycling)
Distal convoluted Tubule • Reabsorbs water, NaCl, and bicarbonate • About 10% of the filtered sodium is reabsorbed in the distal tubule • Maintains acid base balance by secreting hydrogen ions • Site of ADH (Anti-diuretic hormone) and aldosterone mechanisms of action (ADH influences water re-absorption and aldosterone influences sodium re- absorption) • Thiazides inhibit the sodium reabsorption in the distal tubule and lead to a mild diuresis without loss of calcium
Apical transporters FunctionNaCl CT Na uptake, Cl uptake
Collecting duct • The permeability of the collecting ducts for water lead to a concentration of the urine up to the fivefold osmolarity of the plasma • The permeability of the collecting ducts is regulated with ADH (antidiuretic hormone, Vasopressin). ADH causes the incorporation of additional water channels (aquaporins) into the luminal membrane • ADH can control 10% of the primary urine volume, thus can regulate the diuresis between 1–20 l/d.
• Additional sodium reabsorption takes place in the collecting ducts via luminal sodium channels.• The energy for the sodium reabsorption derives from the basolateral sodium- potassium pump.• Aldosterone regulates the sodium and water reabsorption and potassium secretion via expression of the sodium channels and the basolateral sodium- potassium pump.• The luminal sodium channels can be inhibited by amiloride, a potassium-sparing diuretic
Apical transporters FunctionNa channel (ENaC) Na uptake