Skip to main content
SpringerLink
Log in

Regulation of glomerulotubular balance: flow-activated proximal tubule function

  • Invited review
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

The purpose of this review is to summarize our knowledge and understanding of the physiological importance and the mechanisms underlying flow-activated proximal tubule transport. Since the earliest micropuncture studies of mammalian proximal tubule, it has been recognized that tubular flow is an important regulator of sodium, potassium, and acid-base transport in the kidney. Increased fluid flow stimulates Na+ and HCO3 − absorption in the proximal tubule via stimulation of Na/H-exchanger isoform 3 (NHE3) and H+-ATPase. In the proximal tubule, brush border microvilli are the major flow sensors, which experience changes in hydrodynamic drag and bending moment as luminal flow velocity changes and which transmit the force of altered flow to cytoskeletal structures within the cell. The signal to NHE3 depends upon the integrity of the actin cytoskeleton; the signal to the H+-ATPase depends upon microtubules. We have demonstrated that alterations in fluid drag impact tubule function by modulating ion transporter availability within the brush border membrane of the proximal tubule. Beyond that, there is evidence that transporter activity within the peritubular membrane is also modulated by luminal flow. Secondary messengers that regulate the flow-mediated tubule function have also been delineated. Dopamine blunts the responsiveness of proximal tubule transporters to changes in luminal flow velocity, while a DA1 antagonist increases flow sensitivity of solute reabsorption. IP3 receptor-mediated intracellular Ca2+ signaling is critical to transduction of microvillus drag. In this review, we summarize our findings of the regulatory mechanism of flow-mediated Na+ and HCO3 − transport in the proximal tubule and review available information about flow sensing and regulatory mechanism of glomerulotubular balance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Alpern RJ, Cogan MG, Rector FC Jr (1983) Flow dependence of proximal tubular bicarbonate absorption. Am J Phys 245:F478–F484

    CAS  Google Scholar 

  2. Aperia AC (2000) Intrarenal dopamine: a key signal in the interactive regulation of sodium metabolism. Annu Rev Physiol 62:621–647

    Article  CAS  PubMed  Google Scholar 

  3. Baeyens N, Bandyopadhyay C, Coon BG, Yun S, Schwartz MA (2016) Endothelial fluid shear stress sensing in vascular health and disease. J Clin Invest 126:821–828

    Article  PubMed  PubMed Central  Google Scholar 

  4. Baines AD, Chan W (1980) Production of urine free dopamine from DOPA; a micropuncture study. Life Sci 26:253–259

    Article  CAS  PubMed  Google Scholar 

  5. Baines AD, Drangova R, Hatcher C (1985) Dopamine production by isolated glomeruli and tubules from rat kidneys. Can J Physiol Pharmacol 63:155–158

    Article  CAS  PubMed  Google Scholar 

  6. Ball SG, Gunn IG, Douglas IH (1982) Renal handling of dopa, dopamine, norepinephrine, and epinephrine in the dog. Am J Phys 242:F56–F62

    CAS  Google Scholar 

  7. Bertorello A, Aperia A (1990) Inhibition of proximal tubule Na[+]-K[+]-ATPase activity requires simultaneous activation of DA1 and DA2 receptors. Am J Phys 259:F924–F928

    CAS  Google Scholar 

  8. Brown GP, Douglas JG (1982) Angiotensin II binding sites on isolated rat renal brush border membranes. Endocrinology 111:1830–1836

    Article  CAS  PubMed  Google Scholar 

  9. Brown GP, Douglas JG (1983) Angiotensin II-binding sites in rat and primate isolated renal tubular basolateral membranes. Endocrinology 112:2007–2014

    Article  CAS  PubMed  Google Scholar 

  10. Burg MB, Orloff J (1968) Control of fluid absorption in the renal proximal tubule. J Clin Invest 47:2016–2024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Carey RM (2001) Theodore Cooper lecture: renal dopamine system: paracrine regulator of sodium homeostasis and blood pressure. Hypertension 38:297–302

    Article  CAS  PubMed  Google Scholar 

  12. Cervenka L, Mitchell KD, Oliverio MI, Coffman TM, Navar LG (1999) Renal function in the AT1A receptor knockout mouse during normal and volume-expanded conditions. Kidney Int 56:1855–1862

    Article  CAS  PubMed  Google Scholar 

  13. Chan YL, Biagi B, Giebisch G (1982) Control mechanisms of bicarbonate transport across the rat proximal convoluted tubule. Am J Phys 242:F532–F543

    CAS  Google Scholar 

  14. Du Z, Duan Y, Yan Q, Weinstein AM, Weinbaum S, Wang T (2004) Mechanosensory function of microvilli of the kidney proximal tubule. Proc Natl Acad Sci U S A 101:13068–13073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Du Z, Wan L, Yan Q, Weinbaum S, Weinstein AM, Wang T (2012) Regulation of glomerulotubular balance: II: impact of angiotensin II on flow-dependent transport. Am J Physiol 303:F1507–F1516

    CAS  Google Scholar 

  16. Du Z, Weinbaum S, Weinstein AM, Wang T (2015) Regulation of glomerulotubular balance. III. Implication of cytosolic calcium in flow-dependent proximal tubule transport. Am J Physiol 308:F839–F847

    CAS  Google Scholar 

  17. Du Z, Yan Q, Duan Y, Weinbaum S, Weinstein AM, Wang T (2006) Axial flow modulates proximal tubule NHE3 and H-ATPase activities by changing microvillus bending moments. Am J Physiol 290:F289–F296

    CAS  Google Scholar 

  18. Du Z, Yan Q, Wan L, Weinbaum S, Weinstein AM, Wang T (2012) Regulation of glomerulotubular balance. I. Impact of dopamine on flow-dependent transport. Am J Physiol 303:F386–F395

    CAS  Google Scholar 

  19. Duan Y, Weinstein AM, Weinbaum S, Wang T (2010) Shear stress-induced changes of membrane transporter localization and expression in mouse proximal tubule cells. Proc Natl Acad Sci U S A 107:21860–21865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Foskett JK, White C, Cheung KH, Mak DO (2007) Inositol trisphosphate receptor Ca2+ release channels. Physiol Rev 87:593–658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Friedman PA, Figueiredo JF, Maack T, Windhager EE (1981) Sodium-calcium interactions in the renal proximal convoluted tubule of the rabbit. Am J Phys 240:F558–F568

    CAS  Google Scholar 

  22. Gertz KH, and Boylan JW. (1973) Glomerular-tubular balance. In: Handbook of Physiology Section 8:Renal Physiology, edited by J Orloff and RW Berliner pp. 763–790

  23. Green R, Moriarty RJ, Giebisch G (1981) Ionic requirements of proximal tubular fluid reabsorption flow dependence of fluid transport. Kidney Int 20:580–587

    Article  PubMed  Google Scholar 

  24. Guo P, Weinstein AM, Weinbaum S (2000) A hydrodynamic mechanosensory hypothesis for brush border microvilli. Am J Physiol 279:F698–F712

    CAS  Google Scholar 

  25. Hoffman BD, Grashoff C, Schwartz MA (2011) Dynamic molecular processes mediate cellular mechanotransduction. Nature 475:316–323

    Article  CAS  PubMed  Google Scholar 

  26. Hu MC, Fan L, Crowder LA, Karim-Jimenez Z, Murer H, Moe OW (2001) Dopamine acutely stimulates Na+/H+ exchanger [NHE3] endocytosis via clathrin-coated vesicles: dependence on protein kinase A-mediated NHE3 phosphorylation. J Biol Chem 276:26906–26915

    Article  CAS  PubMed  Google Scholar 

  27. Liu FY, Cogan MG (1988) Angiotensin II stimulation of hydrogen ion secretion in the rat early proximal tubule. Modes of action, mechanism, and kinetics. J Clin Invest 82:601–607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu FY, Cogan MG (1988) Flow dependence of bicarbonate transport in the early [S 1] proximal convoluted tubule. Am J Phys 254:F851–F855

    CAS  Google Scholar 

  29. Liu W, Morimoto T, Woda C, Kleyman TR, Satlin LM (2007) Ca2+ dependence of flow-stimulated K secretion in the mammalian cortical collecting duct. Am J Physiol 293:F227–F235

    CAS  Google Scholar 

  30. Liu W, Xu S, Woda C, Kim P, Weinbaum S, Satlin LM (2003) Effect of flow and stretch on the [Ca2+]i response of principal and intercalated cells in cortical collecting duct. Am J Physiol 285:F998–F1012

    Article  CAS  Google Scholar 

  31. Loot AE, Popp R, Fisslthaler B, Vriens J, Nilius B, Fleming I (2008) Role of cytochrome P450-dependent transient receptor potential V4 activation in flow-induced vasodilatation. Cardiovasc Res 80:445–452

    Article  CAS  PubMed  Google Scholar 

  32. Maunsbach AB, and Christensen EI. (1992) Functional ultrastructure of the proximal tubule. In: Handbook of Physiology Renal Physiology 1, chapt. 2: 41–107

  33. Maunsbach AB, Giebisch GH, Stanton BA (1987) Effects of flow rate on proximal tubule ultrastructure. Am J Phys 253:F582–F587

    CAS  Google Scholar 

  34. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiol Rev 78:189–225

    CAS  PubMed  Google Scholar 

  35. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33:129–137

    Article  CAS  PubMed  Google Scholar 

  36. Praetorius HA, Spring KR (2003) The renal cell primary cilium functions as a flow sensor. Curr Opin Nephrol Hypertens 12:517–520

    Article  PubMed  Google Scholar 

  37. Raghavan V, Weisz OA (2016) Discerning the role of mechanosensors in regulating proximal tubule function. Am J Physiol 310:F1–F5

    CAS  Google Scholar 

  38. Schnermann J, Wahl M, Liebau G, Fischbach H (1968) Balance between tubular flow rate and net fluid reabsorption in the proximal convolution of the rat kidney. I. Dependency of reabsorptive net fluid flux upon proximal tubular surface area at spontaneous variations of filtration rate. Pflugers Arch 304:90–103

    Article  CAS  PubMed  Google Scholar 

  39. Seri I, Kone BC, Gullans SR, Aperia A, Brenner BM, Ballermann BJ (1990) Influence of Na+ intake on dopamine-induced inhibition of renal cortical Na[+]-K[+]-ATPase. Am J Phys 258:F52–F60

    CAS  Google Scholar 

  40. Sharif-Naeini R, Dedman A, Folgering JH, Duprat F, Patel A, Nilius B, Honore E (2008) TRP channels and mechanosensory transduction: insights into the arterial myogenic response. Pflugers Arch 456:529–540

    Article  CAS  PubMed  Google Scholar 

  41. Shuai J, Pearson JE, Foskett JK, Mak DO, Parker I (2007) A kinetic model of single and clustered IP3 receptors in the absence of Ca2+ feedback. Biophys J 93:1151–1162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. von Baeyer H, Haeberle DA, van Liew JB, Hare D (1980) Glomerular tubular balance of renal D-glucose transport during hyperglycemia: clearance and micropuncture studies on its characterisation at saturated transport conditions. Pflugers Arch 384:39–47

    Article  Google Scholar 

  43. Wang T (2006) Flow-activated transport events along the nephron. Curr Opin Nephrol Hypertens 15:530–536

    Article  PubMed  Google Scholar 

  44. Wang T, Chan YL (1990) Mechanism of angiotensin II action on proximal tubular transport. J Pharmacol Exp Ther 252:689–695

    CAS  PubMed  Google Scholar 

  45. Wang T, Hropot M, Aronson PS, Giebisch G (2001) Role of NHE isoforms in mediating bicarbonate reabsorption along the nephron. Am J Physiol 281:F1117–F1122

    CAS  Google Scholar 

  46. Wang T, Yang CL, Abbiati T, Schultheis PJ, Shull GE, Giebisch G, Aronson PS (1999) Mechanism of proximal tubule bicarbonate absorption in NHE3 null mice. Am J Phys 277:F298–F302

    CAS  Google Scholar 

  47. Weinbaum S, Duan Y, Satlin LM, Wang T, Weinstein AM (2010) Mechanotransduction in the renal tubule. Am J Physiol 299:F1220–F1236

    CAS  Google Scholar 

  48. Weinman EJ, Shenolikar S (1993) Regulation of the renal brush border membrane Na[+]-H+ exchanger. Annu Rev Physiol 55:289–304

    Article  CAS  PubMed  Google Scholar 

  49. Weinstein AM (1990) Glomerulotubular balance in a mathematical model of the proximal nephron. Am J Phys 258:F612–F626

    CAS  Google Scholar 

  50. Weinstein AM, Weinbaum S, Duan Y, Du Z, Yan Q, Wang T (2007) Flow-dependent transport in a mathematical model of rat proximal tubule. Am J Physiol 292:F1164–F1181

    CAS  Google Scholar 

  51. Wesson LG (1973) Glomerulotubular balance: history of a name. Kidney Int 4:236–238

    Article  CAS  PubMed  Google Scholar 

  52. Woda CB, Leite M Jr, Rohatgi R, Satlin LM (2002) Effects of luminal flow and nucleotides on [Ca[2+]][i] in rabbit cortical collecting duct. Am J Physiol 283:F437–F446

    CAS  Google Scholar 

  53. Wong PS, Johns EJ (1998) The receptor subtype mediating the action of angiotensin II on intracellular sodium in rat proximal tubules. Br J Pharmacol 124:41–46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Xie MH, Liu FY, Wong PC, Timmermans PB, Cogan MG (1990) Proximal nephron and renal effects of DuP 753, a nonpeptide angiotensin II receptor antagonist. Kidney Int 38:473–479

    Article  CAS  PubMed  Google Scholar 

  55. Zhang MZ, Yao B, Wang S, Fan X, Wu G, Yang H, Yin H, Yang S, Harris RC (2011) Intrarenal dopamine deficiency leads to hypertension and decreased longevity in mice. J Clin Invest 121:2845–2854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhuo J, Harris PJ, Skinner SL (1986) Modulation of proximal tubular reabsorption by angiotensin II. Clin Exp Pharmacol Physiol 13:277–281

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This investigation was supported by Public Health Service Grants RO1-DK62289 (T. Wang) and RO1-DK-29857 (A.M. Weinstein) from the National Institute of Diabetes and Digestive and Kidney Diseases.

Author information

Authors and Affiliations

  1. Department of Cellular and Molecular Physiology, Yale University, 333 Cedar Street, New Haven, CT, 06520, USA

    Tong Wang

  2. Department of Biomedical Engineering, City College of New York, CUNY, New York, NY, USA

    Sheldon Weinbaum

  3. Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY, USA

    Alan M. Weinstein

Authors
  1. Tong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sheldon Weinbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alan M. Weinstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tong Wang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, T., Weinbaum, S. & Weinstein, A.M. Regulation of glomerulotubular balance: flow-activated proximal tubule function. Pflugers Arch - Eur J Physiol 469, 643–654 (2017). https://doi.org/10.1007/s00424-017-1960-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-017-1960-8

Keywords

Search

Navigation