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Proximal renal tubule physiology
The proximal tubule reabsorbs approximately 60-65% of the filtered load, including sodium, chloride, bicarbonate, potassium, glucose, and amino acids. Transport occurs through both transcellular and paracellular pathways. Glucose is actively transported across the apical membrane via sodium-glucose co-transporters and exits across the basolateral membrane. Sodium is reabsorbed primarily via the sodium-potassium ATPase pump. Bicarbonate is reabsorbed through secretion of hydrogen ions via sodium-hydrogen exchange and reabsorption of bicarbonate. The proximal tubule also plays an important role in reabsorption of other substances like phosphate, calcium, magnesium and
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Proximal renal tubule physiology
- 1. PROXIMAL TUBULAR PHYSIOLOGY Ahad Lodhi Mentor: Dr Karniski
- 2. Mechanism of Transport 1. Primary Active Transport 2. Secondary Active Transport 3. Pinocytosis 4. Passive Transport
- 4. Two pathways ofthe absorption: Lumen Plasma Cells Transcellular Pathway Paracellular transport
- 5. • The proximaltubule is often divided into: Ultrastructural Pars convoluta (PCT)(convoluted part) Proximal straight tubule (PST) (straight part) Histological S1-segment S2-segment S3-segment
- 6. Reabsorb about 65percent of the filtered sodium, chloride, bicarbonate, and potassium and essentially al the filtered glucose and amino acids. Secrete organic acids, bases, and hydrogen ions into the tubular lumen.
- 7. • The mainfunction of the proximal tubule is the isosmotic reabsorption of about 60-65% of the glomerular filtrate. • Quantitatively, however, marked differences exist along the tubule: – reabsorption of sodium, water, glucose and bicarbonate in the early proximal tubule (S1) is about three-fold greater than that in the mid-portion of the convoluted proximal tubule (S2), and nearly ten times that of the straight segment of the tubule (S3). – All segments of the proximal tubule are capable of reabsorbing the same solutes . – Proximal tubular reabsorption therefore plays a crucial role in the maintenance of fluid and electrolyte balance of the body
- 8. Objectives of thelecture Proximal tubular function Proximal tubular handling of Glucose Na with Cl, Potassium Phosphate Calcium Magnesium Amino acid Bicarbonate & H+ Urea Water
- 9. Filtration, reabsorption, andexcretion rates of substances by the kidneys Filtered Reabsorbed Excreted Reabsorbed (meq/24h) (meq/24h) (meq/24h) (%) Glucose (g/day) 180 180 0 100 Bicarbonate (meq/day) 4,320 4,318 2 > 99.9 Sodium (meq/day) 25,560 25,410 150 99.4 Chloride (meq/day) 19,440 19,260 180 99.1 Water (l/day) 169 167.5 1.5 99.1 Urea (g/day) 48 24 24 50 Creatinine (g/day) 1.8 0 1.8 0
- 10. Proximal convoluted tubulePCT Reabsorption of • 65% of Na+ ( 1ry active) • 65 % of K+ (2ry active), water, urea & Cl- (secondary active and passive) • 100% of glucose & amino acids ( 2ry active) • 90% Ca • Po4 , Mg+, nitrate, sulfate • Bicarbonate formed inside the cell from carbonic acids by the help of carbonic anhydrase to give HCO3&H2 HCO3 is reabsorbed &H2 is secreted
- 11. Transport of solutesout of the proximal tubule can be described to occur in two phases. In the first phase, essential nutrients such as glucose, sodium bicarbonate, and amino acids are predominantly reabsorbed. The second phase predominantly involves NaCl reabsorption
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- 15. Glucose reabsorption •Glucose reabsorption in the proximal tubule occurs in two steps – Carrier mediated, Na/glucose co-transport across the apical membrane • Followed by facilitated glucose transport and active sodium extrusion • Two specific Na coupled carriers have been identified in the apical membrane -SGLT-1 and SGLT-2
- 16. Figure 1 Glucosereabsorption in the proximal tubule Mather, A. & Pollock, C. (2010) Renal glucose transporters: novel targets for hyperglycemia management Nat. Rev. Nephrol. doi:10.1038/nrneph.2010.38
- 18. • These dependon the sodium gradient and glucose transport is therefore a secondary active step as sodium gradient has to be actively maintained. • Transport of glucose across the basolateral membrane involves the GLUT i.e. GLUT 2 in the early PT and GLUT 1 in the late PT
- 19. SGLT & GLUT • Glucose reabsorption is maximum in the S1 segment and slows as the tubular fluid progresses from S1 to S3. • However the affinity for glucose rises from S1 to S3 as indicated by the Km – (Km is defined as the concentration of substrate at which a half-maximal rate of transport is attained) – The Km for S1 is about 2 mM and for S3 it is 0.4 mM • The different affinities for glucose in the different proximal segments is due to the presence of the two SGLT carriers, i.e. 1 and 2.
- 20. SGLT & GLUT • SGLT-2 has a high capacity but low affinity and is found in the early proximal tubule, whereas SGLT-1 has high affinity but low capacity and is found in the late proximal tubule. • As the early part of the proximal tubule is in the outer cortex,SGLT-2 is found predominantly located there, whereas SGLT-1is found located in the outer medulla, where S3 is located • Exit of glucose from the proximal tubular cells is via GLUT, in particular GLUT2 , which is a high-capacity, low affinity baso-lateral transporter found in tissues with large glucose fluxes, such as intestine, liver, pancreas and proximal tubule (S1 and S2) . • Fanconi Syndrome: GLUT 2 Mutation
- 21. Sodium and chloride(Na and Cl) Reabsorption
- 23. • The majority(70%) of sodium is reabsorbed in the proximal tubule. It is reabsorbed into the cytosol of the epithelial cells either alone by diffusion through ion channels followed by water or together with another product such as chloride, glucose or AA using a co-transporter by secondary active co-transport. • First Phase: Along with glucose, amino acids Phosphate and bicarbonate in the early part of the proximal tubule(co-transporter) secondary active • Second Phase (along with chloride): Active & Passive involving electric (ion channels) and concentration gradient resulting in ATP utilization and diffusion.
- 24. • Sodium chloridereabsorption occurs along the entire nephron • The percentage of NaCl absorption varies from one third to two thirds of the total NaCl absorption in the second phase of proximal absorption
- 25. Nacl • Historically,sodium reabsorptive pathways have been emphasized over chloride, but in truth, both ions must be reabsorbed to defend or expand extracellular volume and, in fact, some authors have argued that chloride balance actually takes precedence over sodium in determining extracellular volume and blood pressure • In the proximal tubule, chloride reabsorption is indirectly linked to sodium reabsorption through potential and concentration gradients resulting from active sodium transport
- 26. • Passive ParacellularChloride Transport in the Proximal Tubule • Paracellular chloride flux can consist of two components: – diffusion driven by the electrochemical chloride gradient, and – solvent drag driven by convective forces resulting from bulk solvent flow. Solvent drag has been invoked since early days of renal physiology although the bulk of evidence indicates that solvent drag does not play a significant role in sodium chloride reabsorption
- 27. Active Transcellular Chloride Transport in the Proximal Tubule • Apical chloride entry pathways Warnock and Yee demonstrated the presence of bicarbonate-independent chloride-base (presumably hydroxide) exchange in brush border vesicles that could support such a transport model
- 28. chloride/formate exchange •Karniski and Aronson found that rabbit brush border vesicles contain Cl-formate exchange activity • In the case of formate recycling, the process appears to be indirectly coupled to sodium transport through activity of the apical sodium-proton exchanger NHE3 and the consequent acidification of the luminal fluid • NHE3 supports electroneutral exchange of sodium ions for protons. The inwardly directed sodium gradient generated by the sodium-potassium ATPase thus drives extrusion of protons and acidification of the luminal fluid. • The low pH in the lumen would result in a fraction of the extruded formate becoming protonated to formic acid, which as a small uncharged molecule, has some significant membrane permeability and could diffuse into the cell across the apical membrane.
- 29. chloride-oxalate exchanger •oxalate-driven transport is not inhibited by blockers of NHE3 or in the NHE3 knockout mice • acidification-independent recycling pathway • oxalate-dependent absorption was found to require not only active sodium transport but also lumenal sulfate • Proximal tubule brush border vesicles were found to exhibit anion exchange activity that could exchange oxalate for sulfate • Brush border sulfate uptake is carried out by a sodium-sulfate cotransporter (due to Na gradient) that carries two sodium ions and one sulfate ion into the cell • The high intracellular concentration of sulfate drives oxalate into the cell via a sulfate-oxalate exchanger, and the resulting elevated intracellular concentration of oxalate drives chloride into the cell via the chloride-oxalate exchanger
- 30. Basolateral chloride exitpathways Possible pathways for chloride exit across the basolateral membrane of proximal tubule cells, including a • chloride channel (top), • a potassium chloride cotransporter (middle), • a sodium dependent chloride bicarbonate exchanger (bottom)
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- 34. • At ablood pH of 7.4, 80% of the ionized phosphate is HPO4-2 and rest H2PO4- • At a GFR of 180 l/day approximately 7000 mg of phosphate is filtered per day. Nearly 90% of the filtered phosphate is reabsorbed. • The proximal tubule reabsorbs 80% of the filtered load • Phosphate reabsorption is sodium dependent and enters the apical membrane by secondary active transport and leaves the basolateral membrane passively
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- 37. • The proximaltubule reabsorbs about 50-60% of the filtered calcium • The transcellular reabsorption probably accounts for about 10-15%of the total calcium reabsorption in the proximal tubule and present in the S1 segment of the PCT
- 38. • Calcium reabsorptionin the S2 segment of the proximal tubule is mainly passive and paracellular • It parallels the reabsorption of sodium and water • Claudin-2 is proposed to be the paracellular calcium channel • There is also a possibility that there is active transport of Ca 2+,which is transcellular involving passive movement of calcium into the cell through epithelial calcium channels and then a basolateral extrusion by Na+/Ca2+ exchanger driven by Na+- K +ATPase or Ca2+- ATPase.
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- 41. The Secretion ofH+ and the Reabsorption of HCO3 -
- 43. The Secretion ofH+ • The secretion of H+ in this section of the nephron is mainly a result of the Na+/H+ exchanger – This is an antiporter in the apical membrane – Energy for this process is provided by the Na/K ATPase in the basolateral membrane – Therefore it is secondary active transport – The ATPase pumps sodium out of the cell into the interstitium – This maintains a low intracellular Na which creates a gradient for the absorption of sodium by the Na+/H+ antiporter – This allows it to drive H against its concentration gradient – Maintains a negative intracellular potential – It is essential that HCO3 - is removed from the cells by the co-transporter with sodium to ensure efficient H+ secretion.
- 44. Reabsorption of HCO3 - • Very efficient reabsorption mechanism • 90% in first 1-2mm of tubule • Lots of luminal carbonic anhydrase • Stops the accumulation of H2CO3 in the lumen • Keeps H+ concentration low - helps antiporter • Roles of carbonic anhydrase - from h20 and CO2 – In the cell forms HCO3 – In the tubule it works in reverse forming CO2 and H2O from the intermediate H2CO3 which forms from HCO3 - and H+ – Allows continuous H+ secretion and HCO3 - reabsorption
- 45. Urea • 50%of filtered urea is reabsorbed in the proximal tubule. However the concentration of urea actually increases thanks to the reabsorption of 70% of the filtered water in the same portion of the nephron. Urea is not able to be reabsorbed from this point until it reaches the lower portion of the collecting duct therefore its concentration further increases with the reabsorption of water.
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- 49. passive reabsorption orsecretion depending upon the urine pH • Salicylic acid, for example, exists both as the intact acid and the organic anion • Salicylic acid <—> H+ + salicylate- • The intact acid, but not the organic anion, can freely diffuse across cell membranes because it is nonpolar • This difference makes salicylate excretion pH-dependent • Raising the urine pH (which lowers the free H+ concentration) will shift the above reaction to the right. The ensuing fall in the urinary salicylic acid concentration will minimize the back diffusion of secreted salicylic acid out of the tubular lumen, thereby increasing total drug excretion
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- 51. The transepithelial waterpermeability (Pf) of the proximal tubule is very high, which allows small osmotic pressure differences to drive water transport. • Both paracellular and transcellular pathways are believed to be involved in the movement of water. The transcellular pathway is more dominant and involves aquaporins
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