Proximal Tubule Flashcards
1
Q
Kidney maintenance of ECF
A
- the kidney maintains ECF solute and fluid volume (water) homeostasis by a process of separating solute and water from plasma (filtration) and returning solute and water to the plasma (reabsorption)
- the amount of solute and water returned to the plasma (reabsorption) depends on the prevailing balance between the amount of solute and water consumed and the amount of solute and water exiting the ECF by respiration, sweating, defecation and urination
- each segment of the nephron may be considered for its constitutive and regulatory function with regard to the renal handling of solutes and water. Constitutive function occurs with little regulation and mediates a less renal response to changes in solute or fluid (water) balance.
- the regulatory function of the different segments of the nephron mediates the renal response to changes in solute or fluid (water) balance
2
Q
Proximal tubule- general
A
- nephron segment mediating reabsorption of 67% of both filtered water as well as filtered NaCL
- most of the reabsorption is constitutive and may increase only when severely volume depleted
- when proximal tubule fluid reabsorption occurs isomotically, without a change in NaCl concentration in the 33% of the tubular fluid remaining in PT
- the PT is leaky epithelium permitting rapid equilibration of solutes and water (osmosis) across the epithelium
3
Q
Organic solutes and Proximal tubule
A
- the PT is the nephron segment mediating reabsorption of most of the organic solute filtered from the plasma (glucose, amino acids, mono- and dicarboxylates, vitamins) as well as bicarbonate and some inorganic solutes (phosphate, sulfate)
- most organic solute reabsorption is constitutive and saturable. Importantly, most reabsorption of organic solutes occurs in the Pt, and little reabsorption occurs in the nephron downstream. Accordingly these solutes will appear in the urine if not reabsorbed by the PT
- the PT is the nephron segment mediating secretion of organic anions (drug metabolites) from the peritubular capillaries (blood) to the luminal fluid where they remain and are excreted in the urine
4
Q
Changes in Solute Composition from Early to Late Proximal Tubule
A
- TF/P is the ratio of solute concentration in the tubular fluid (TF) relative to the solute concentration in the plasma (P)
- inulin is freely filtered at the glomerulus and is neither reabsorbed from nor secreted into the tubular fluid and is effectively trapped in the tubular fluid
- an increase in TF/P for inulin indicates an increased concentration of inulin in the tubular fluid resulting from the reabsorption of water from the tubular fluid
- a TF/P of close to 1 for Na+ indicates the essentially equivalent reabsorption of Na+ and water from the proximal tubular fluid resulting in a constant Na+ concentration in the tubular fluid
- 67% of the filtered Na+ and water is reabsorbed in the proximal tubule, the Na+ concentration in the proximal tubule fluid does not change and remains essentially constant
- the increase in TF/P for Cl- reflects the preferential reabsorption of HCO3- rather than Cl- in the early PT
- the decrease in TF/O for HCO3-, animo acids and glucose indicates reabsorption from the tubule fluid which contributes, as osmotic equivalents, to driving the reabsorption of water
5
Q
Voltage with Proximal Tubule
A
- the change in transepithelail voltage from -3 mV at the beginning of the PT to +3 mV downstream results from the exit of more positive cationic charged solutes in first 25% of the proximal tubule and the exit of negative anionic charge than positive cationic charge from the tubular fluid
- the slight excess of positive charge remaining in the tubular fluid in the form cations, creates the lumen positive transepithelial voltage difference measured across the tubule cell layer
- -3 mV at beginning to +3 mV results from the net efflux and reabsorption of more positively charged, cationic solutes in the first 25% of the PT and the net efflux and reabsorption of more negatively charged, anionic solutes downstream in the remaining 75% of the PT
- the slight excess of negative or positive charge remaining in the tubular fluid in the form cations, creates the lumen positive transepithelial voltage difference in the first 25% of the PT and creates the lumen negative transepithelial voltage difference, “downstream” in the remaining 75% of the PT
6
Q
Proximal Tubule
A
- Na+ and Cl- transport across the proximal tubule cell layer from the tubular fluid in the tubular lumen to the peritubular fluid at the basal side of the proximal tubule cell layer
- Na and Cl- transport across the proximal tubule cell layer may be transcellular, resulting from the uptake across the luminal membrane and efflux across the basal membrane
- or paracellular, resulting from movement of Na+ and Cl- between cells through tight junctions
- driving forces for both transcellular and paracellular Na+ transport across the early proximal tubule where the transepithelial voltage difference is lumen negative
7
Q
Proximal tubule Na and CL Reabsorption
A
- transepithelial transport of Na+ in the PT occurs both between cells (paracellular) as well as across the cell (transcellular) mediated by uptake at the apical (lumenal) membrane and efflux at the basal and lateral membrane
- transcellular Na+ transport results from passive uptake of Na+ across the apical membrane down a Na+ electrochemical gradient and active efflux of Na+ across the basal and lateral membrane against a Na+ electrochemical gradient. A lumen negative transepithelail voltage difference serves to drive a paracellular “backleak” of Na+ in the early PT and approximately 33% of Na+ transported transcellularly leaks back into the lumen. In the late PT the tranepithelial voltage difference reverses and a lumen positive transepithelial voltage differences serves to drive paracellular Na+ transport from lumen to the peritubular space
- passive uptake of Na+ across the PT apical membrane by cotransport
- multiple, substrate specific, Na+-solute symporters function in the apical membrane as a pathway for cellular Na+ uptake as well as concentrative accumulation of intracellular solutes such as glucose, amino acids, mono- and dicarboxylates, vitamins, phosphate and sulfate. The net positive charge transfer resulting from Na+-solute symport creates a lumen negative transepithelial voltage difference, which drives a paracellular “backleak” of Na+ from the peritubular space into the lumen. A Na+ solute antiporter mediates the exchange of lumenal Na+ for intracellular H+ across the apical membrane
- the active efflux of Na+ across the PT basal and lateral membrane occurs by primary active transport mediated by a Na+-K+ ATPase and by secondary active transport mediated by Na+-HCO3- symport
8
Q
Transcellular vs Paracellular transport of Na+ and Cl-
A
- transepithelial transport of Cl- in the PT occurs both between cells (paracellular) in the early and late PT as well as across the cell (transcellular) mediated by uptake at the apical (lumenal) membrane and efflux at the basal and lateral membrane in the late PT
- paracellular Cl- transport in the early PT is driven by a lumen negative transepithelial voltage difference. Due to preferential HCO3 reabsorption in the early PT, lumenal Cl- concentration is elevated above plasma Cl- concentration in the late PT and an outward, transepithelial Cl- concentration gradient exists driving passive paracellular efflux of lumenal CL-. The paracellular efflux of Cl- creates a lumen positive diffusion potential, which in turn drives paracellular efflux of Na+ in the late PT
- transcellular Cl- mediates most transepithelial Cl- transport in the late PT. The active uptake of Cl- across the PT apical membrane occurs by Cl- solute antiport driven by an outwardly directed anion (formate, oxalate, HCo3-, OH) concentration gradient. The passive efflux of intracellular Cl- across the basolateral membrane is mediated by a Cl- channel and by a K+-Cl- symporter
9
Q
Water Reabsorption Proximal Tubule
A
- most 67% of the glomerular filtrate is returned to the circulation at the proximal tubule where reabsorption of tubular fluid occurs without a change in osmolarity. PT transepithelial reabsorption of water is passive and occurs between cells (paracellular) as well as across cells (transcellular). The primary driving force for paracellular and transcellular water reabsorption in the small osmotic gradient resulting from active solute (primarily Na+ and Cl-) reabsorption across the PT
- the exceptionally high water permeability (leakiness) of the PT permits a large lumen to peritubule movement of water in response to a small osmotic gradient. The high transcellular water permeability is due to the presence of water (aquaporin) channels in both the apical and basolateral membrane of PT cells. Most PT transepithelial water reabsorption occurs by the transcellular pathway driven osmotically by transcellular solute reabsorption
- water absorption from the peritubular space into the peritubular capillaries is driven by a net difference in Starling forces favoring absorption into the peritubular capillaries
- the paracellular movement of water from lumen to peritubular space driven by the active Na+ transport-dependent increase in osmolarity in the lateral space entrains or “sweeps” Na+ and Cl- within the flow in the direction of the peritubular capillary by a process of solvent drag
10
Q
Regulation of Proximal Tubule Na+, Cl- and Water Reabsorption
A
- changes in renal hemodynamics, increasing or decreasing GFR, increase or decrease the filtered load of Na+ into the PT. The PT responds by reabsorbing a constant fraction of the Na+ filtered load (67%), constituitively, independent of external neural or hormonal control
- this process of glomerulotubular (GT) balance serves to maintain Na+ and fluid balance and defend against excessive Na+ and fluid loss or gain
- Angiotensin II and renal sympathetic nerve activity increase PT Na+ and water reabsorption when circulating volume is reduced
11
Q
Role of Proximal Tubule in Acid-Base Homeostasis
A
- reabsorb and return most (85%) filtered HCO3- to the circulation maintaining ECF HCO3- concentration constant (24 mM). The PT reabsorption is mostly constitutive
- secrete H+ generated from: metabolism of amino acids, production of organic acids such as lactic acid or acetoacetate, beta-hydroxybutyrate, or intestinal HCO3- loss. The loss of HCO3- may decrease ECF pH
- the process of secreting H+ generates “new” HCO3-, which replaces HCO3- lost in buffering of organic and inorganic acid
12
Q
Proximal Tubule HCO3 Reabsorption
A
- the process of proximal tubular HCO3- reabsorption is transcellular and mostly constituitive, returning most of the filtered HCO3- to the circulation with little regulation. Transcellular PT HCO3- reabsorption is coupled to transcellular Na+ reabsorption by a process, which involves a recycling of H+ across the luminal membrane. In the PT tubular fluid, filtered HCO3- is dehydrated by a lumenal membrane carbonic anhydrase to form CO2 and OH-
- H+ transported out of the cell by a luminal membrane Na+/H+ antiporter titrates OH- to form H2O, which moves into the cell. CO2 diffuses across the luminal membrane into the cell and is combined with intracellular OH- by intracellular carbonic anhydrase to form intracellular HCO3-.
- the source of intracellular OH- arises from H+ transported out of the cell by a luminal membrane Na+/H+ antiporter, which leaves behind an intracellular OH- for each H+ transported out of the cell. Intracellular Na+ is actively transported out of the cell across the basolateral membrane by a Na+/K+ ATPase. Intracellular Na+ is also actively transported out of the cell across the basolateral membrane by a Na+-HCO3- symporter, which also mediates efflux of intracellular HCO3-
- transcellular transport process mediating HCO3 reabsorption does NOT involve net secretion of H+ which recycle back and forth across the luminal membrane
- the transcellular transport process mediating HCO3- reabsorption I saturable and increasingly greater amounts of filtered HCO3- will alkalinize the tubular fluid and appear in the urine as plasma HCO3- concentration exceeds a reabsorptive threshold of 40 mM
- ECF volume contraction stimulates HCO3- resorption due to an effect of the Starling forces increasing PT fluid reabsorption and an effect of increased angiotensin II to increase luminal membrane Na+-H+ antiport resulting in increased Na+ and HCO3- reabsorption
13
Q
Proximal Tubule H+ Secretion
A
- the proximal tubule participates in the renal excretion of H+ ions as (1) titratable acid (10-30 mEq/day) and as (2) NH4+ (30-50 mEq/day)
- the renal excretion of H+ as titratable acid arises in the proximal tubule from the titration of dibasic phosphoric acid to monobasic phosphoric acid. The pK of phosphoric acid makes it an excellent buffer of H+ the pH of the PT fluid (7.4 to 6.8)
- the renal excretion of H+ as NH4+ arises in the proximal tubule from the titration of NH3 to NH4+. The proximal tubule, thick ascending loop of Henle and the collecting duct participate in the excretion of H+ and NH4+. In the PT, the origin of NH3 is intracellular glutamine metabolism secondary to active glutamine uptake across the luminal and basolateral membrane
14
Q
Proximal Tubule Excretion of H+ as Titratable Acid
A
- Not all the protons transported across the lumenal membrane by the Na+-H+ antiporter and the H+-ATPase titrates filtered bicarbonate to begin the process of transcellular, constituitive bicarbonate reabsorption
- a smaller fraction of the protons transported across the lumenal membrane titrates filtered phosphate from the dibasic to monobasic buffer ion species. In this instance, the resulting deficit of intracellular protons and excess of hydroxyl ions drives the creation by mass action of NEW bicarbonate, to be distinguished from filtered bicarbonate
- this NEW bicarbonate is returned to the circulation to stoichiometrically replace each of the bicarbonate ions lost in the titration of protons generated throughout the body by cellular metabolism
- thus by a process of titratable acid excretion, protons generated by metabolism are ultimately excreted in the urine by titration of filtered phosphate and generation of NEW bicarbonate
15
Q
Proximal Tubule excretion of H+ as NH4+
A
- in addition to proton excretion as titratable acid (H2PO4-) protons secreted by the proximal tubule are also excreted as ammonium. Ammonium excretion mediated by the proximal tubule arises from the intracellular metabolism of glutamine
- glutaminase and further metabolism of alpha-ketoglutarate generate intracellular ammonia and hydroxyl ion. Due to its pK (9,2) intracellular NH3 arising from glutamine metabolism is rapidly titrated to NH4+ at intracellular pH.
- the luminal membrane Na+/H+ antiporter transports NH4+ as well as H+ in exchange for Na+ across the membrane and mediates efflux of intracellular NH4+
- a smaller amount of intracellular NH3 freely diffuses across the lumenal membrane into the tubular fluid where it is trapped by titration to NH4+. The protons titrating NH3 to NH4+ in the proximal tubular fluid arise from the Na+/H+ exchanger or the H+-ATPase transporting H+ transport across the lumenal membrane
- most important, for each NH3 titrated to NH4, a proton is trapped and excreted in the urine and a NEW HCO3 ion is made inside the proximal tubule cell for return to the circulation. Similar to the process of titratable acid excretion this NEW bicarbonate replaces the HCO3 ion replaces HCO3 ion is lost in the buffering of metabolic acid. Thus, by titratable acid and ammonium excretion, the generation of NEW HCO3- continuously replenishes the depletion of HCO3- in the ECF, as acid generated from metabolism is buffered by HCO3- maintaining pH constant
