Sensing of tubular flow and renal electrolyte transport


The kidney is a remarkable organ that accomplishes the challenge of removing waste from the body and simultaneously regulating electrolyte and water balance. Pro-urine flows through the nephron in a highly dynamic manner and adjustment of the reabsorption rates of water and ions to the variable tubular flow is required for electrolyte homeostasis. Renal epithelial cells sense the tubular flow by mechanosensation. Interest in this phenomenon has increased in the past decade since the acknowledgement of primary cilia as antennae that sense renal tubular flow. However, the significance of tubular flow sensing for electrolyte handling is largely unknown. Signal transduction pathways regulating flow-sensitive physiological responses involve calcium, purinergic and nitric oxide signalling, and are considered to have an important role in renal electrolyte handling. Given that mechanosensation of tubular flow is an integral role of the nephron, defective tubular flow sensing is probably involved in renal disease. Studies investigating tubular flow and electrolyte transport differ in their methodology, subsequently hampering translational validity. This Review provides the basis for understanding electrolyte disorders originating from altered tubular flow sensing as a result of pathological conditions.

Key points

  • Renal tubular flow is highly variable owing to the glomerular filtration rate, tubuloglomerular feedback, renal pelvic wall contraction and fluid reabsorption along the nephron.

  • To regulate water and electrolyte balance, adjustment of water and electrolyte reabsorption rates is required according to the variable tubular flow.

  • Renal epithelial cells contain specialized sensing machinery that transduces changes in tubular flow into a cellular response that regulates water and electrolyte transport.

  • Tubular flow regulates renal water and electrolyte transport along the different segments of the nephron.

  • Discerning how renal water and electrolyte handling is affected by tubular flow is essential in understanding how aberrant tubular flow sensing could result in pathophysiological conditions.

  • Improved understanding of renal tubular flow dynamics will aid the development of novel therapeutic options for diseases related to tubular flow sensing.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Flow-sensing machinery in the kidney.
Fig. 2: Mechanosensitive signalling pathways affecting electrolyte reabsorption.
Fig. 3: Urinary flow sensing and electrolyte transport along the nephron.
Fig. 4: Schematic overview of tubular flow characteristics in the kidney.


  1. 1.

    Pollak, M. R., Quaggin, S. E., Hoenig, M. P. & Dworkin, L. D. The glomerulus: the sphere of influence. Clin. J. Am. Soc. Nephrol. 9, 1461–1469 (2014).

    PubMed  Google Scholar 

  2. 2.

    Schnermann, J., Wright, F. S., Davis, J. M., Stackelberg, W. V. & Grill, G. Regulation of superficial nephron filtration rate by tubulo-glomerular feedback. Pflugers Arch. 318, 147–175 (1970).

    CAS  PubMed  Google Scholar 

  3. 3.

    Gilmer, G. G., Deshpande, V., Chou, C.-L. & Knepper, M. A. Flow resistance along the rat renal tubule. Am. J. Physiol. Renal Physiol. 315, F1398–F1405 (2018).

    CAS  PubMed  Google Scholar 

  4. 4.

    Sakai, T., Craig, D. A., Wexler, A. S. & Marsh, D. J. Fluid waves in renal tubules. Biophys. J. 50, 805–813 (1986).

    CAS  PubMed  Google Scholar 

  5. 5.

    Reinking, L. N. & Schmidt-Nielsen, B. Peristaltic flow of urine in the renal papillary collecting ducts of hamsters. Kidney Int. 20, 55–60 (1981).

    CAS  PubMed  Google Scholar 

  6. 6.

    Holstein-Rathlou, N. H. & Marsh, D. J. Oscillations of tubular pressure, flow, and distal chloride concentration in rats. Am. J. Physiol. Renal Physiol. 256, F1007–F1014 (1989).

    CAS  Google Scholar 

  7. 7.

    Vallon, V. Tubuloglomerular feedback and the control of glomerular filtration rate. Physiology 18, 169–174 (2003).

    CAS  Google Scholar 

  8. 8.

    Schnermann, J., Wahl, M., Liebau, G. & Fischbach, H. Balance between tubular flow rate and net fluid reabsorption in the proximal convolution of the rat kidney. Pflugers Arch. 304, 90–103 (1968).

    CAS  PubMed  Google Scholar 

  9. 9.

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

    PubMed  Google Scholar 

  10. 10.

    Fitzgibbons, J. P., Gennari, F. J., Garfinkel, H. B. & Cortell, S. Dependence of saline-induced natriuresis upon exposure of the kidney to the physical effects of extracellular fluid volume expansion. J. Clin. Invest. 54, 1428–1436 (1974).

    CAS  PubMed  Google Scholar 

  11. 11.

    Nakano, D. et al. Reduction of tubular flow rate as a mechanism of oliguria in the early phase of endotoxemia revealed by intravital imaging. J. Am. Soc. Nephrol. 26, 3035–3044 (2015).

    CAS  PubMed  Google Scholar 

  12. 12.

    Corman, B., Roinel, N. & De Rouffignac, C. Water reabsorption capacity of the proximal convoluted tubule: a microperfusion study on rat kidney. J. Physiol. 316, 379–392 (1981).

    CAS  PubMed  Google Scholar 

  13. 13.

    Frick, A., Rumrich, G., Ullrich, K. J. & Lassiter, W. E. Microperfusion study of calcium transport in the proximal tubule of the rat kidney. Pflugers Arch. Gesamte Physiol. Menschen Tiere 286, 109–117 (1965).

    CAS  PubMed  Google Scholar 

  14. 14.

    Bank, N., Aynedjian, H. S. & Weinstein, S. W. A microperfusion study of phosphate reabsorption by the rat proximal renal tubule. Effect of parathyroid hormone. J. Clin. Invest. 54, 1040–1048 (1974).

    CAS  PubMed  Google Scholar 

  15. 15.

    Chan, Y. L., Biagi, B. & Giebisch, G. Control mechanisms of bicarbonate transport across the rat proximal convoluted tubule. Am. J. Physiol. 242, F532–F543 (1982).

    CAS  PubMed  Google Scholar 

  16. 16.

    Alpern, R. J., Cogan, M. G. & Rector, F. C. Flow dependence of proximal tubular bicarbonate absorption. Am. J. Physiol. 245, F478–F484 (1983).

    CAS  PubMed  Google Scholar 

  17. 17.

    Liu, F. Y. & Cogan, M. G. Flow dependence of bicarbonate transport in the early (S1) proximal convoluted tubule. Am. J. Physiol. 254, F851–F855 (1988).

    CAS  PubMed  Google Scholar 

  18. 18.

    Palmer, L. G. & Schnermann, J. Integrated control of Na transport along the nephron. Clin. J. Am. Soc. Nephrol. 10, 676–687 (2015).

    CAS  PubMed  Google Scholar 

  19. 19.

    Good, D. W. & Wright, F. S. Luminal influences on potassium secretion: sodium concentration and fluid flow rate. Am. J. Physiol. 236, F192–F205 (1979).

    CAS  PubMed  Google Scholar 

  20. 20.

    Engbretson, B. G. & Stoner, L. C. Flow-dependent potassium secretion by rabbit cortical collecting tubule in vitro. Am. J. Physiol. 253, F896–F903 (1987).

    CAS  PubMed  Google Scholar 

  21. 21.

    Sata, Y., Head, G. A., Denton, K., May, C. N. & Schlaich, M. P. Role of the sympathetic nervous system and its modulation in renal hypertension. Front. Med. 5, 82 (2018).

    Google Scholar 

  22. 22.

    Hansen, P. B., Castrop, H., Briggs, J. & Schnermann, J. Adenosine induces vasoconstriction through Gi-dependent activation of phospholipase C in isolated perfused afferent arterioles of mice. J. Am. Soc. Nephrol. 14, 2457–2465 (2003).

    CAS  PubMed  Google Scholar 

  23. 23.

    Kohan, D. E., Inscho, E. W., Wesson, D. & Pollock, D. M. Physiology of endothelin and the kidney. Compr. Physiol. 1, 883–919 (2011).

    PubMed  Google Scholar 

  24. 24.

    Fattah, H., Layton, A. & Vallon, V. How do kidneys adapt to a deficit or loss in nephron number? Physiology 34, 189–197 (2019).

    CAS  PubMed  Google Scholar 

  25. 25.

    Carrisoza-Gaytan, R. et al. Effects of biomechanical forces on signaling in the cortical collecting duct (CCD). Am. J. Physiol. Renal Physiol. 307, F195–F204 (2014).

    CAS  PubMed  Google Scholar 

  26. 26.

    Liu, W. et al. Effect of flow and stretch on the [Ca2+]i response of principal and intercalated cells in cortical collecting duct. Am. J. Physiol. Renal Physiol. 285, F998–F1012 (2003).

    CAS  PubMed  Google Scholar 

  27. 27.

    Weinbaum, S., Duan, Y., Satlin, L. M., Wang, T. & Weinstein, A. M. Mechanotransduction in the renal tubule. Am. J. Physiol. Renal Physiol. 299, F1220–F1236 (2010).

    CAS  PubMed  Google Scholar 

  28. 28.

    Sgouralis, I. & Layton, A. T. Control and modulation of fluid flow in the rat kidney. Bull. Math. Biol. 75, 2551–2574 (2013).

    PubMed  Google Scholar 

  29. 29.

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

    CAS  PubMed  Google Scholar 

  30. 30.

    Du, Z. et al. Mechanosensory function of microvilli of the kidney proximal tubule. Proc. Natl Acad. Sci. USA 101, 13068–13073 (2004).

    CAS  PubMed  Google Scholar 

  31. 31.

    Alenghat, F. J., Nauli, S. M., Kolb, R., Zhou, J. & Ingber, D. E. Global cytoskeletal control of mechanotransduction in kidney epithelial cells. Exp. Cell Res. 301, 23–30 (2004).

    CAS  PubMed  Google Scholar 

  32. 32.

    Duan, Y. et al. Shear-induced reorganization of renal proximal tubule cell actin cytoskeleton and apical junctional complexes. Proc. Natl Acad. Sci. USA 105, 11418–11423 (2008).

    CAS  PubMed  Google Scholar 

  33. 33.

    Green, K. & Otori, T. Direct measurements of membrane unstirred layers. J. Physiol. 207, 93–102 (1970).

    CAS  PubMed  Google Scholar 

  34. 34.

    Dainty, J. & Ginzburg, B. Z. Irreversible thermodynamics and frictional models of membrane processes, with particular reference to the cell membrane. J. Theor. Biol. 5, 256–265 (1963).

    CAS  PubMed  Google Scholar 

  35. 35.

    Missner, A. et al. Carbon dioxide transport through membranes. J. Biol. Chem. 283, 25340–25347 (2008).

    CAS  PubMed  Google Scholar 

  36. 36.

    Endeward, V. & Gros, G. Extra- and intracellular unstirred layer effects in measurements of CO2 diffusion across membranes–a novel approach applied to the mass spectrometric 18O technique for red blood cells. J. Physiol. 587, 1153–1167 (2009).

    CAS  PubMed  Google Scholar 

  37. 37.

    Praetorius, H. A. & Spring, K. R. The renal cell primary cilium functions as a flow sensor. Curr. Opin. Nephrol. Hypertens. 12, 517–520 (2003).

    PubMed  Google Scholar 

  38. 38.

    Bulger, R. E., Siegel, F. L. & Pendergrass, R. Scanning and transmission electron microscopy of the rat kidney. Am. J. Anat. 139, 483–501 (1974).

    CAS  PubMed  Google Scholar 

  39. 39.

    Wilson, P. D., Geng, L., Li, X. & Burrow, C. R. The PKD1 gene product, ‘polycystin-1,’ is a tyrosine-phosphorylated protein that colocalizes with alpha2beta1-integrin in focal clusters in adherent renal epithelia. Lab. Invest. 79, 1311–1323 (1999).

    CAS  PubMed  Google Scholar 

  40. 40.

    Yoder, B. K., Hou, X. & Guay-Woodford, L. M. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J. Am. Soc. Nephrol. 13, 2508–2516 (2002).

    CAS  PubMed  Google Scholar 

  41. 41.

    Streets, A. J., Wagner, B. E., Harris, P. C., Ward, C. J. & Ong, A. C. M. Homophilic and heterophilic polycystin 1 interactions regulate E-cadherin recruitment and junction assembly in MDCK cells. J. Cell. Sci. 122, 1410–1417 (2009).

    CAS  PubMed  Google Scholar 

  42. 42.

    Kunnen, S. J. et al. Comparative transcriptomics of shear stress treated Pkd1-/- cells and pre-cystic kidneys reveals pathways involved in early polycystic kidney disease. Biomed. Pharmacother. 108, 1123–1134 (2018).

    CAS  PubMed  Google Scholar 

  43. 43.

    O’Neil, R. G. & Heller, S. The mechanosensitive nature of TRPV channels. Pflugers Arch. 451, 193–203 (2005).

    PubMed  Google Scholar 

  44. 44.

    Zhou, Y. & Greka, A. Calcium-permeable ion channels in the kidney. Am. J. Physiol. Renal Physiol. 310, F1157–F1167 (2016).

    CAS  PubMed  Google Scholar 

  45. 45.

    Wu, L., Gao, X., Brown, R. C., Heller, S. & O’Neil, R. G. Dual role of the TRPV4 channel as a sensor of flow and osmolality in renal epithelial cells. Am. J. Physiol. Renal Physiol. 293, F1699–F1713 (2007).

    CAS  PubMed  Google Scholar 

  46. 46.

    Berrout, J. et al. Function of transient receptor potential cation channel subfamily V member 4 (TRPV4) as a mechanical transducer in flow-sensitive segments of renal collecting duct system. J. Biol. Chem. 287, 8782–8791 (2012).

    CAS  PubMed  Google Scholar 

  47. 47.

    Mamenko, M., Zaika, O., Boukelmoune, N., O’Neil, R. G. & Pochynyuk, O. Deciphering physiological role of the mechanosensitive TRPV4 channel in the distal nephron. Am. J. Physiol. Renal Physiol. 308, F275–F286 (2015).

    CAS  PubMed  Google Scholar 

  48. 48.

    Praetorius, H. A. & Leipziger, J. intrarenal purinergic signaling in the control of renal tubular transport. Annu. Rev. Physiol. 72, 377–393 (2010).

    CAS  PubMed  Google Scholar 

  49. 49.

    Burnstock, G., Evans, L. C. & Bailey, M. A. Purinergic signalling in the kidney in health and disease. Purinergic Signal. 10, 71–101 (2014).

    CAS  PubMed  Google Scholar 

  50. 50.

    Praetorius, H. A. & Leipziger, J. ATP release from non-excitable cells. Purinergic Signal. 5, 433–446 (2009).

    CAS  PubMed  Google Scholar 

  51. 51.

    Menzies, R. I., Tam, F. W., Unwin, R. J. & Bailey, M. A. Purinergic signaling in kidney disease. Kidney Int. 91, 315–323 (2017).

    CAS  PubMed  Google Scholar 

  52. 52.

    Schnermann, J. & Levine, D. Z. Paracrine factors in tubuloglomerular feedback: adenosine, ATP, and nitric oxide. Annu. Rev. Physiol. 65, 501–529 (2003).

    CAS  PubMed  Google Scholar 

  53. 53.

    Bailey, M. A., Hillman, K. A. & Unwin, R. J. P2 receptors in the kidney. J. Auton. Nerv. Syst. 81, 264–270 (2000).

    CAS  PubMed  Google Scholar 

  54. 54.

    Praetorius, H. A., Frøkiaer, J. & Leipziger, J. Transepithelial pressure pulses induce nucleotide release in polarized MDCK cells. Am. J. Physiol. Renal Physiol. 288, F133–F141 (2005).

    CAS  PubMed  Google Scholar 

  55. 55.

    Jensen, M. E. J., Odgaard, E., Christensen, M. H., Praetorius, H. A. & Leipziger, J. Flow-Induced [Ca2+]i increase depends on nucleotide release and subsequent purinergic signaling in the intact nephron. J. Am. Soc. Nephrol. 18, 2062–2070 (2007).

    CAS  PubMed  Google Scholar 

  56. 56.

    Xu, C. et al. Attenuated, flow-induced ATP release contributes to absence of flow-sensitive, purinergic Cai2+ signaling in human ADPKD cyst epithelial cells. Am. J. Physiol. Renal Physiol. 296, F1464–F1476 (2009).

    CAS  PubMed  Google Scholar 

  57. 57.

    Palygin, O., Evans, L. C., Cowley, A. W. & Staruschenko, A. Acute in vivo analysis of ATP release in rat kidneys in response to changes of renal perfusion pressure. J. Am. Heart Assoc. 6, 492 (2017).

    Google Scholar 

  58. 58.

    Inscho, E. W., Cook, A. K. & Navar, L. G. Pressure-mediated vasoconstriction of juxtamedullary afferent arterioles involves P2-purinoceptor activation. Am. J. Physiol. 271, F1077–F1085 (1996).

    CAS  PubMed  Google Scholar 

  59. 59.

    Wang, N. et al. Paracrine signaling through plasma membrane hemichannels. Biochim. Biophys. Acta 1828, 35–50 (2013).

    CAS  PubMed  Google Scholar 

  60. 60.

    Bjaelde, R. G., Arnadottir, S. S., Overgaard, M. T., Leipziger, J. & Praetorius, H. A. Renal epithelial cells can release ATP by vesicular fusion. Front. Physiol. 4, 238 (2013).

    PubMed  Google Scholar 

  61. 61.

    Svenningsen, P., Burford, J. L. & Peti-Peterdi, J. ATP releasing connexin 30 hemichannels mediate flow-induced calcium signaling in the collecting duct. Front. Physiol. 4, 292 (2013).

    PubMed  Google Scholar 

  62. 62.

    Sipos, A. et al. Connexin 30 deficiency impairs renal tubular ATP release and pressure natriuresis. J. Am. Soc. Nephrol. 20, 1724–1732 (2009).

    CAS  PubMed  Google Scholar 

  63. 63.

    Hanner, F., Lam, L., Nguyen, M. T. X., Yu, A. & Peti-Peterdi, J. Intrarenal localization of the plasma membrane ATP channel pannexin1. Am. J. Physiol. Renal Physiol. 303, F1454–F1459 (2012).

    CAS  PubMed  Google Scholar 

  64. 64.

    Hanner, F., Sorensen, C. M., Holstein-Rathlou, N.-H. & Peti-Peterdi, J. Connexins and the kidney. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R1143–R1155 (2010).

    CAS  PubMed  Google Scholar 

  65. 65.

    Hovater, M. B. et al. Loss of apical monocilia on collecting duct principal cells impairs ATP secretion across the apical cell surface and ATP-dependent and flow-induced calcium signals. Purinergic Signal. 4, 155–170 (2008).

    CAS  PubMed  Google Scholar 

  66. 66.

    Praetorius, H. A. & Leipziger, J. Released nucleotides amplify the cilium-dependent, flow-induced [Ca 2+] iresponse in MDCK cells. Acta Physiol. 197, 241–251 (2009).

    CAS  Google Scholar 

  67. 67.

    Rodat-Despoix, L., Hao, J., Dandonneau, M. & Delmas, P. Shear stress-induced Ca2+ mobilization in MDCK cells is ATP dependent, no matter the primary cilium. Cell Calcium 53, 327–337 (2013).

    CAS  PubMed  Google Scholar 

  68. 68.

    Clemmer, J. S., Pruett, W. A., Coleman, T. G., Hall, J. E. & Hester, R. L. Mechanisms of blood pressure salt sensitivity: new insights from mathematical modeling. Am. J. Physiol. Regul. Integr. Comp. Physiol. 312, R451–R466 (2017).

    PubMed  Google Scholar 

  69. 69.

    Ivy, J. R. & Bailey, M. A. Pressure natriuresis and the renal control of arterial blood pressure. J. Physiol. 592, 3955–3967 (2014).

    CAS  PubMed  Google Scholar 

  70. 70.

    O’Connor, P. M. & Cowley, A. W. Modulation of pressure-natriuresis by renal medullary reactive oxygen species and nitric oxide. Curr. Hypertens. Rep. 12, 86–92 (2010).

    PubMed  Google Scholar 

  71. 71.

    Clapham, D. E. Calcium signaling. Cell 131, 1047–1058 (2007).

    CAS  PubMed  Google Scholar 

  72. 72.

    Woda, C. B., Leite, M., Rohatgi, R. & Satlin, L. M. Effects of luminal flow and nucleotides on [Ca(2+)](i) in rabbit cortical collecting duct. Am. J. Physiol. Renal Physiol. 283, F437–F446 (2002).

    CAS  PubMed  Google Scholar 

  73. 73.

    Liu, W., Morimoto, T., Woda, C., Kleyman, T. R. & Satlin, L. M. Ca2+ dependence of flow-stimulated K secretion in the mammalian cortical collecting duct. Am. J. Physiol. Renal Physiol. 293, F227–F235 (2007).

    CAS  PubMed  Google Scholar 

  74. 74.

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

    CAS  PubMed  Google Scholar 

  75. 75.

    Delling, M. et al. Primary cilia are not calcium-responsive mechanosensors. Nature 531, 656–660 (2016).

    CAS  PubMed  Google Scholar 

  76. 76.

    Hofherr, A. & Köttgen, M. Polycystic kidney disease: cilia and mechanosensation revisited. Nat. Rev. Nephrol. 12, 318–319 (2016).

    CAS  PubMed  Google Scholar 

  77. 77.

    Guimond, J., Mamarbachi, A. M., Allen, B. G., Rindt, H. & Hébert, T. E. Role of specific protein kinase C isoforms in modulation of beta1- and beta2-adrenergic receptors. Cell. Signal. 17, 49–58 (2005).

    CAS  PubMed  Google Scholar 

  78. 78.

    Siso-Nadal, F., Fox, J. J., Laporte, S. A., Hébert, T. E. & Swain, P. S. Cross-talk between signaling pathways can generate robust oscillations in Calcium and cAMP. PLoS One 4, e7189 (2009).

    Google Scholar 

  79. 79.

    Gadsby, D. C., Vergani, P. & Csanády, L. The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 440, 477–483 (2006).

    CAS  PubMed  Google Scholar 

  80. 80.

    Liu, T., Konkalmatt, P. R., Yang, Y. & Jose, P. A. Gastrin decreases Na+,K+-ATPase activity via a PI 3-kinase- and PKC-dependent pathway in human renal proximal tubule cells. Am. J. Physiol. Endocrinol. Metab. 310, E565–E571 (2016).

    PubMed  Google Scholar 

  81. 81.

    Yang, L.-M., Rinke, R. & Korbmacher, C. Stimulation of the epithelial sodium channel (ENaC) by cAMP involves putative ERK phosphorylation sites in the C termini of the channel’s beta- and gamma-subunit. J. Biol. Chem. 281, 9859–9868 (2006).

    CAS  PubMed  Google Scholar 

  82. 82.

    Burnstock, G. Short- and long-term (trophic) purinergic signalling. Philos. Trans. R. Soc. Lond. B Biol. Sci. 371, 20150422 (2016).

    PubMed  Google Scholar 

  83. 83.

    Herrera, M. & Garvin, J. L. Recent advances in the regulation of nitric oxide in the kidney. Hypertension 45, 1062–1067 (2005).

    CAS  PubMed  Google Scholar 

  84. 84.

    Wang, L. et al. Shear stress blunts tubuloglomerular feedback partially mediated by primary cilia and nitric oxide at the macula densa. Am. J. Physiol. Regul. Integr. Comp. Physiol. 309, R757–R766 (2015).

    CAS  PubMed  Google Scholar 

  85. 85.

    Ramseyer, V. D., Ortiz, P. A., Carretero, O. A. & Garvin, J. L. Angiotensin II-mediated hypertension impairs nitric oxide-induced NKCC2 inhibition in thick ascending limbs. Am. J. Physiol. Renal Physiol. 310, F748–F754 (2016).

    CAS  PubMed  Google Scholar 

  86. 86.

    Stuehr, D. J. Mammalian nitric oxide synthases. Biochim. Biophys. Acta 1411, 217–230 (1999).

    CAS  PubMed  Google Scholar 

  87. 87.

    Cabral, P. D., Hong, N. J. & Garvin, J. L. Shear stress increases nitric oxide production in thick ascending limbs. Am. J. Physiol. Renal Physiol. 299, F1185–F1192 (2010).

    CAS  PubMed  Google Scholar 

  88. 88.

    Wheatley, W. & Kohan, D. E. Role for reactive oxygen species in flow-stimulated inner medullary collecting duct endothelin-1 production. Am. J. Physiol. Renal Physiol. 313, F514–F521 (2017).

    CAS  PubMed  Google Scholar 

  89. 89.

    Ortiz, P. A., Hong, N. J. & Garvin, J. L. Luminal flow induces eNOS activation and translocation in the rat thick ascending limb. II. Role of PI3-kinase and Hsp90. Am. J. Physiol. Renal Physiol. 287, F281–F288 (2004).

    CAS  PubMed  Google Scholar 

  90. 90.

    Hyndman, K. A., Bugaj, V., Mironova, E., Stockand, J. D. & Pollock, J. S. NOS1-dependent negative feedback regulation of the epithelial sodium channel in the collecting duct. Am. J. Physiol. Renal Physiol. 308, F244–F251 (2015).

    CAS  PubMed  Google Scholar 

  91. 91.

    Plato, C. F., Stoos, B. A., Wang, D. & Garvin, J. L. Endogenous nitric oxide inhibits chloride transport in the thick ascending limb. Am. J. Physiol. 276, F159–F163 (1999).

    CAS  PubMed  Google Scholar 

  92. 92.

    Ortiz, P. A. & Garvin, J. L. NO Inhibits NaCl absorption by rat thick ascending limb through activation of cGMP-stimulated phosphodiesterase. Hypertension 37, 467–471 (2001).

    CAS  PubMed  Google Scholar 

  93. 93.

    Zheleznova, N. N., Yang, C. & Cowley, A. W. Role of Nox4 and p67phox subunit of Nox2 in ROS production in response to increased tubular flow in the mTAL of Dahl salt-sensitive rats. Am. J. Physiol. Renal Physiol. 311, F450–F458 (2016).

    CAS  PubMed  Google Scholar 

  94. 94.

    Hong, N. J. & Garvin, J. L. Flow increases superoxide production by NADPH oxidase via activation of Na-K-2Cl cotransport and mechanical stress in thick ascending limbs. Am. J. Physiol. Renal Physiol. 292, F993–F998 (2007).

    CAS  PubMed  Google Scholar 

  95. 95.

    O’Connor, P. M. A radical approach to balancing the tides of tubular flow. Am. J. Physiol. Renal Physiol. 307, F917–F918 (2014).

    PubMed  Google Scholar 

  96. 96.

    Abe, M. et al. Effect of sodium delivery on superoxide and nitric oxide in the medullary thick ascending limb. Am. J. Physiol. Renal Physiol. 291, F350–F357 (2006).

    CAS  PubMed  Google Scholar 

  97. 97.

    Juncos, R. & Garvin, J. L. Superoxide enhances Na-K-2Cl cotransporter activity in the thick ascending limb. Am. J. Physiol. Renal Physiol. 288, F982–F987 (2005).

    CAS  PubMed  Google Scholar 

  98. 98.

    Huangfu, D. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83–87 (2003).

    CAS  PubMed  Google Scholar 

  99. 99.

    Breslow, D. K. et al. A CRISPR-based screen for Hedgehog signaling provides insights into ciliary function and ciliopathies. Nat. Genet. 50, 460–471 (2018).

    CAS  PubMed  Google Scholar 

  100. 100.

    Simons, M. et al. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat. Genet. 37, 537–543 (2005).

    CAS  PubMed  Google Scholar 

  101. 101.

    Sheng, X. et al. Effects of FSS on the expression and localization of the core proteins in two Wnt signaling pathways, and their association with ciliogenesis. Int. J. Mol. Med. 42, 1809–1818 (2018).

    CAS  PubMed  Google Scholar 

  102. 102.

    Boehlke, C. et al. Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat. Cell Biol. 12, 1115–1122 (2010).

    CAS  PubMed  Google Scholar 

  103. 103.

    Grahammer, F. et al. mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress. Proc. Natl Acad. Sci. USA 111, E2817–E2826 (2014).

    CAS  PubMed  Google Scholar 

  104. 104.

    Grahammer, F. et al. mTORC2 critically regulates renal potassium handling. J. Clin. Invest. 126, 1773–1782 (2016).

    PubMed  Google Scholar 

  105. 105.

    Grahammer, F. et al. mTOR regulates endocytosis and nutrient transport inproximal tubular cells. J. Am. Soc. Nephrol. 28, 230–241 (2017).

    CAS  PubMed  Google Scholar 

  106. 106.

    Elijovich, F. & Laffer, C. L. Prostaglandin E2 mediates connecting tubule glomerular feedback. Hypertension 63, e19 (2014).

    CAS  PubMed  Google Scholar 

  107. 107.

    De Miguel, C., Speed, J. S., Kasztan, M., Gohar, E. Y. & Pollock, D. M. Endothelin-1 and the kidney: new perspectives and recent findings. Curr. Opin. Nephrol. Hypertens. 25, 35–41 (2016).

    PubMed  Google Scholar 

  108. 108.

    Wesson, L. G. Glomerulotubular balance: history of a name. Kidney Int. 4, 236–238 (1973).

    CAS  PubMed  Google Scholar 

  109. 109.

    Burg, M. B. & Orloff, J. Control of fluid absorption in the renal proximal tubule. J. Clin. Invest. 47, 2016–2024 (1968).

    CAS  PubMed  Google Scholar 

  110. 110.

    Thomson, S. C. & Blantz, R. C. Glomerulotubular balance, tubuloglomerular feedback, and salt homeostasis. J. Am. Soc. Nephrol. 19, 2272–2275 (2008).

    PubMed  Google Scholar 

  111. 111.

    Du, Z. et al. Axial flow modulates proximal tubule NHE3 and H-ATPase activities by changing microvillus bending moments. Am. J. Physiol. Renal Physiol. 290, F289–F296 (2006).

    CAS  PubMed  Google Scholar 

  112. 112.

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

    CAS  PubMed  Google Scholar 

  113. 113.

    Maddox, D. A., Fortin, S. M., Tartini, A., Barnes, W. D. & Gennari, F. J. Effect of acute changes in glomerular filtration rate on Na+/H+ exchange in rat renal cortex. J. Clin. Invest. 89, 1296–1303 (1992).

    CAS  PubMed  Google Scholar 

  114. 114.

    Preisig, P. A. Luminal flow rate regulates proximal tubule H-HCO3 transporters. Am. J. Physiol. 262, F47–F54 (1992).

    CAS  PubMed  Google Scholar 

  115. 115.

    Bailey, M. A. Inhibition of bicarbonate reabsorption in the rat proximal tubule by activation of luminal P2Y1 receptors. Am. J. Physiol. Renal Physiol. 287, F789–F796 (2004).

    CAS  PubMed  Google Scholar 

  116. 116.

    Castrop, H. Mediators of tubuloglomerular feedback regulation of glomerular filtration: ATP and adenosine. Acta Physiol. 189, 3–14 (2007).

    CAS  Google Scholar 

  117. 117.

    Cabral, P. D., Hong, N. J. & Garvin, J. L. ATP mediates flow-induced NO production in thick ascending limbs. Am. J. Physiol. Renal Physiol. 303, F194–F200 (2012).

    CAS  PubMed  Google Scholar 

  118. 118.

    Song, J. et al. Role of the primary cilia on the macula densa and thick ascending limbs in regulation of sodium excretion and hemodynamics. Hypertension 70, 324–333 (2017).

    CAS  PubMed  Google Scholar 

  119. 119.

    Mount, D. B. Thick ascending limb of the loop of Henle. Clin. J. Am. Soc. Nephrol. 9, 1974–1986 (2014).

    CAS  PubMed  Google Scholar 

  120. 120.

    Saez, F., Hong, N. J. & Garvin, J. L. NADPH oxidase 4-derived superoxide mediates flow-stimulated NKCC2 activity in thick ascending limbs. Am. J. Physiol. Renal Physiol. 314, F934–F941 (2018).

    CAS  PubMed  Google Scholar 

  121. 121.

    Hong, N. J. & Garvin, J. L. Endogenous flow-induced superoxide stimulates Na/H exchange activity via PKC in thick ascending limbs. Am. J. Physiol. Renal Physiol. 307, F800–F805 (2014).

    CAS  PubMed  Google Scholar 

  122. 122.

    Fry, B. C., Edwalards, A. & Layton, A. T. Impact of nitric-oxide-mediated vasodilation and oxidative stress on renal medullary oxygenation: a modeling study. Am. J. Physiol. Renal Physiol. 310, F237–F247 (2016).

    CAS  PubMed  Google Scholar 

  123. 123.

    Emans, T. W., Janssen, B. J., Joles, J. A. & Krediet, C. T. P. Nitric oxide synthase inhibition induces renal medullary hypoxia in conscious rats. J. Am. Heart Assoc. 7, e009501 (2018).

    CAS  PubMed  Google Scholar 

  124. 124.

    Subramanya, A. R. & Ellison, D. H. Distal convoluted tubule. Clin. J. Am. Soc. Nephrol. 9, 2147–2163 (2014).

    CAS  PubMed  Google Scholar 

  125. 125.

    de Baaij, J. H. F., Hoenderop, J. G. J. & Bindels, R. J. M. Magnesium in man: implications for health and disease. Physiol. Rev. 95, 1–46 (2015).

    PubMed  Google Scholar 

  126. 126.

    Verschuren, E. H. J., Hoenderop, J. G. J., Peters, D. J. M., Arjona, F. J. & Bindels, R. J. M. Tubular flow activates magnesium transport in the distal convoluted tubule. FASEB J. 33, 5034–5044 (2018).

  127. 127.

    Sahni, J. & Scharenberg, A. M. The SLC41 family of MgtE-like magnesium transporters. Mol. Aspects Med. 34, 620–628 (2013).

    CAS  PubMed  Google Scholar 

  128. 128.

    Wabakken, T., Rian, E., Kveine, M. & Aasheim, H.-C. The human solute carrier SLC41A1 belongs to a novel eukaryotic subfamily with homology to prokaryotic MgtE Mg2+ transporters. Biochem. Biophys. Res. Commun. 306, 718–724 (2003).

    CAS  PubMed  Google Scholar 

  129. 129.

    Arjona, F. J. et al. SLC41A1 is essential for magnesium homeostasis in vivo. Pflugers Arch. 471, 845–860 (2019).

    CAS  PubMed  Google Scholar 

  130. 130.

    de Baaij, J. H. F. et al. Identification of SLC41A3 as a novel player in magnesium homeostasis. Sci. Rep. 6, 28565 (2016).

    PubMed  Google Scholar 

  131. 131.

    Dai, L.-J., Kang, H. S., Kerstan, D., Ritchie, G. & Quamme, G. A. ATP inhibits Mg 2+uptake in MDCT cells via P2X purinoceptors. Am. J. Physiol. Renal Physiol. 281, F833–F840 (2001).

    CAS  PubMed  Google Scholar 

  132. 132.

    de Baaij, J. H. F. et al. P2X4 receptor regulation of transient receptor potential melastatin type 6 (TRPM6) Mg2+ channels. Pflugers Arch. 466, 1941–1952 (2014).

    PubMed  Google Scholar 

  133. 133.

    Lambers, T. T., Bindels, R. J. M. & Hoenderop, J. G. J. Coordinated control of renal Ca2+ handling. Kidney Int. 69, 650–654 (2006).

    CAS  PubMed  Google Scholar 

  134. 134.

    van der Hagen, E. A. E. et al. Coordinated regulation of TRPV5-mediated Ca2+ transport in primary distal convolution cultures. Pflugers Arch. 466, 2077–2087 (2014).

    PubMed  Google Scholar 

  135. 135.

    Costanzo, L. S. & Windhager, E. E. Calcium and sodium transport by the distal convoluted tubule of the rat. Am. J. Physiol. 235, F492–F506 (1978).

    CAS  PubMed  Google Scholar 

  136. 136.

    Bonny, O. & Edwards, A. Calcium reabsorption in the distal tubule: regulation by sodium, pH, and flow. Am. J. Physiol. Renal Physiol. 304, F585–F600 (2013).

    CAS  PubMed  Google Scholar 

  137. 137.

    van Baal, J. et al. Hormone-stimulated Ca2+ transport in rabbit kidney: multiple sites of inhibition by exogenous ATP. Am. J. Physiol. 277, F899–F906 (1999).

    PubMed  Google Scholar 

  138. 138.

    Mohammed, S. G. et al. Fluid shear stress increases transepithelial transport of Ca2+ in ciliated distal convoluted and connecting tubule cells. FASEB J. 31, 1796–1806 (2017).

    CAS  PubMed  Google Scholar 

  139. 139.

    Carrisoza-Gaytan, R., Carattino, M. D., Kleyman, T. R. & Satlin, L. M. An unexpected journey: conceptual evolution of mechanoregulated potassium transport in the distal nephron. Am. J. Physiol. Cell Physiol. 310, C243–C259 (2016).

    PubMed  Google Scholar 

  140. 140.

    Kunau, R. T., Webb, H. L. & Borman, S. C. Characteristics of the relationship between the flow rate of tubular fluid and potassium transport in the distal tubule of the rat. J. Clin. Invest. 54, 1488–1495 (1974).

    PubMed  Google Scholar 

  141. 141.

    Khuri, R. N., Strieder, W. N. & Giebisch, G. Effects of flow rate and potassium intake on distal tubular potassium transfer. Am. J. Physiol. 228, 1249–1261 (1975).

    CAS  PubMed  Google Scholar 

  142. 142.

    Malnic, G., Berliner, R. W. & Giebisch, G. Flow dependence of K+ secretion in cortical distal tubules of the rat. Am. J. Physiol. Renal Physiol. 256, F932–F941 (1989).

    CAS  Google Scholar 

  143. 143.

    Malnic, G., Berliner, R. W. & Giebisch, G. Distal perfusion studies: transport stimulation by native tubule fluid. Am. J. Physiol. 258, F1523–F1527 (1990).

    CAS  PubMed  Google Scholar 

  144. 144.

    Taniguchi, J. & Imai, M. Flow-dependent activation of maxi K + channels in apical membrane of rabbit connecting tubule. J. Membr. Biol. 164, 35–45 (1998).

    CAS  PubMed  Google Scholar 

  145. 145.

    Grimm, P. R. & Sansom, S. C. BK channels in the kidney. Curr. Opin. Nephrol. Hypertens. 16, 430–436 (2007).

    CAS  PubMed  Google Scholar 

  146. 146.

    Grimm, P. R., Foutz, R. M., Brenner, R. & Sansom, S. C. Identification and localization of BK-β subunits in the distal nephron of the mouse kidney. Am. J. Physiol. Renal Physiol. 293, F350–F359 (2007).

    CAS  PubMed  Google Scholar 

  147. 147.

    Pluznick, J. L., Wei, P., Grimm, P. R. & Sansom, S. C. BK-β1 subunit: immunolocalization in the mammalian connecting tubule and its role in the kaliuretic response to volume expansion. Am. J. Physiol. Renal Physiol. 288, F846–F854 (2005).

    CAS  PubMed  Google Scholar 

  148. 148.

    Rieg, T. et al. The role of the BK channel in potassium homeostasis and flow-induced renal potassium excretion. Kidney Int. 72, 566–573 (2007).

    CAS  PubMed  Google Scholar 

  149. 149.

    Bailey, M. A. et al. Maxi-K channels contribute to urinary potassium excretion in the ROMK-deficient mouse model of Type II Bartter’s syndrome and in adaptation to a high-K diet. Kidney Int. 70, 51–59 (2006).

    CAS  PubMed  Google Scholar 

  150. 150.

    Ren, Y., Garvin, J. L., Liu, R. & Carretero, O. A. Crosstalk between the connecting tubule and the afferent arteriole regulates renal microcirculation. Kidney Int. 71, 1116–1121 (2007).

    CAS  PubMed  Google Scholar 

  151. 151.

    Wang, H., Garvin, J. L., D’Ambrosio, M. A., Ren, Y. & Carretero, O. A. Connecting tubule glomerular feedback antagonizes tubuloglomerular feedback in vivo. Am. J. Physiol. Renal Physiol. 299, F1374–F1378 (2010).

    CAS  PubMed  Google Scholar 

  152. 152.

    Ren, Y., D’Ambrosio, M. A., Garvin, J. L., Wang, H. & Carretero, O. A. Possible mediators of connecting tubule glomerular feedback. Hypertension 53, 319–323 (2009).

    CAS  PubMed  Google Scholar 

  153. 153.

    Pearce, D. et al. Collecting duct principal cell transport processes and their regulation. Clin. J. Am. Soc. Nephrol. 10, 135–146 (2015).

    CAS  PubMed  Google Scholar 

  154. 154.

    Roy, A., Al-bataineh, M. M. & Pastor-Soler, N. M. Collecting duct intercalated cell function and regulation. Clin. J. Am. Soc. Nephrol. 10, 305–324 (2015).

    CAS  PubMed  Google Scholar 

  155. 155.

    Mohammed, S. G. et al. Primary cilia–regulated transcriptome in the renal collecting duct. FASEB J. 32, 3653–3668 (2018).

    CAS  PubMed  Google Scholar 

  156. 156.

    Woda, C. B., Bragin, A., Kleyman, T. R. & Satlin, L. M. Flow-dependent K +secretion in the cortical collecting duct is mediated by a maxi-K channel. Am. J. Physiol. Renal Physiol. 280, F786–F793 (2001).

    CAS  PubMed  Google Scholar 

  157. 157.

    Carrisoza-Gaytan, R. et al. The mechanosensitive BKα/β1 channel localizes to cilia of principal cells in rabbit cortical collecting duct (CCD). Am. J. Physiol. Renal Physiol. 312, F143–F156 (2017).

    CAS  PubMed  Google Scholar 

  158. 158.

    Woda, C. B. et al. Ontogeny of flow-stimulated potassium secretion in rabbit cortical collecting duct: functional and molecular aspects. Am. J. Physiol. Renal Physiol. 285, F629–F639 (2003).

    CAS  PubMed  Google Scholar 

  159. 159.

    Palmer, L. G. & Frindt, G. High-conductance K channels in intercalated cells of the rat distal nephron. Am. J. Physiol. Renal Physiol. 292, F966–F973 (2007).

    CAS  PubMed  Google Scholar 

  160. 160.

    Liu, W. et al. Role of NKCC in BK channel-mediated net K+ secretion in the CCD. Am. J. Physiol. Renal Physiol. 301, F1088–F1097 (2011).

    CAS  PubMed  Google Scholar 

  161. 161.

    Morla, L., Doucet, A., Lamouroux, C., Crambert, G. & Edwards, A. The renal cortical collecting duct: a secreting epithelium? J. Physiol. 594, 5991–6008 (2016).

    CAS  PubMed  Google Scholar 

  162. 162.

    Holtzclaw, J. D., Cornelius, R. J., Hatcher, L. I. & Sansom, S. C. Coupled ATP and potassium efflux from intercalated cells. Am. J. Physiol. Renal Physiol. 300, F1319–F1326 (2011).

    CAS  PubMed  Google Scholar 

  163. 163.

    Li, Y. et al. Expression of a diverse array of Ca2+-Activated K+ channels (SK1/3, IK1, BK) that functionally couple to the mechanosensitive TRPV4 channel in the collecting duct system of kidney. PLoS One 11, e0155006 (2016).

    PubMed  Google Scholar 

  164. 164.

    Mamenko, M. V. et al. The renal TRPV4 channel is essential for adaptation to increased dietary potassium. Kidney Int. 91, 1398–1409 (2017).

    CAS  PubMed  Google Scholar 

  165. 165.

    Feraille, E. & Dizin, E. Coordinated control of ENaC and Na+,K+-ATPase in renal collecting duct. J. Am. Soc. Nephrol. 27, 2554–2563 (2016).

    CAS  PubMed  Google Scholar 

  166. 166.

    Morimoto, T. et al. Mechanism underlying flow stimulation of sodium absorption in the mammalian collecting duct. Am. J. Physiol. Renal Physiol. 291, F663–F669 (2006).

    CAS  PubMed  Google Scholar 

  167. 167.

    Satlin, L. M., Sheng, S., Woda, C. B. & Kleyman, T. R. Epithelial Na(+) channels are regulated by flow. Am. J. Physiol. Renal Physiol. 280, F1010–F1018 (2001).

    CAS  PubMed  Google Scholar 

  168. 168.

    Althaus, M., Bogdan, R., Clauss, W. G. & Fronius, M. Mechano-sensitivity of epithelial sodium channels (ENaCs): laminar shear stress increases ion channel open probability. FASEB J. 21, 2389–2399 (2007).

    CAS  PubMed  Google Scholar 

  169. 169.

    Ernandez, T., Udwan, K., Chassot, A., Martin, P.-Y. & Feraille, E. Uninephrectomy and apical fluid shear stress decrease ENaC abundance in collecting duct principal cells. Am. J. Physiol. Renal Physiol. 314, F763–F772 (2018).

    CAS  PubMed  Google Scholar 

  170. 170.

    Koster, H. P., Hartog, A., van Os, C. H. & Bindels, R. J. Inhibition of Na+ and Ca2+ reabsorption by P2u purinoceptors requires PKC but not Ca2+ signaling. Am. J. Physiol. Renal Physiol. 270, F53–F60 (1996).

    CAS  Google Scholar 

  171. 171.

    Rieg, T. et al. Mice lacking P2Y2 receptors have salt-resistant hypertension and facilitated renal Na+ and water reabsorption. FASEB J. 21, 3717–3726 (2007).

    CAS  PubMed  Google Scholar 

  172. 172.

    Stockand, J. D. et al. Purinergic inhibition of ENaC produces aldosterone escape. J. Am. Soc. Nephrol. 21, 1903–1911 (2010).

    CAS  PubMed  Google Scholar 

  173. 173.

    Pochynyuk, O. et al. Dietary Na+ inhibits the open probability of the epithelial sodium channel in the kidney by enhancing apical P2Y 2-receptor tone. FASEB J. 24, 2056–2065 (2010).

    CAS  PubMed  Google Scholar 

  174. 174.

    Arroyo, J. P. & Gamba, G. Advances in WNK signaling of salt and potassium metabolism: clinical implications. Am. J. Nephrol. 35, 379–386 (2012).

    CAS  PubMed  Google Scholar 

  175. 175.

    Kwon, T. H., Frøkiaer, J., Han, J. S., Knepper, M. A. & Nielsen, S. Decreased abundance of major Na(+) transporters in kidneys of rats with ischemia-induced acute renal failure. Am. J. Physiol. Renal Physiol. 278, F925–F939 (2000).

    CAS  PubMed  Google Scholar 

  176. 176.

    Vallon, V. Tubular transport in acute kidney injury: relevance for diagnosis, prognosis and intervention. Nephron 134, 160–166 (2016).

    PubMed  Google Scholar 

  177. 177.

    Morrell, E. D., Kellum, J. A., Hallows, K. R. & Pastor-Soler, N. M. Epithelial transport during septic acute kidney injury. Nephrol. Dial. Transplant. 29, 1312–1319 (2014).

    CAS  PubMed  Google Scholar 

  178. 178.

    Bellomo, R., Kellum, J. A. & Ronco, C. Acute kidney injury. Lancet 380, 756–766 (2012).

    PubMed  Google Scholar 

  179. 179.

    Bragadottir, G., Redfors, B. & Ricksten, S.-E. Mannitol increases renal blood flow and maintains filtration fraction and oxygenation in postoperative acute kidney injury: a prospective interventional study. Crit. Care 16, R159–R159 (2012).

    PubMed  Google Scholar 

  180. 180.

    Lee, D. L. et al. Posttranslational regulation of NO synthase activity in the renal medulla of diabetic rats. Am. J. Physiol. Renal Physiol. 288, F82–F90 (2005).

    CAS  PubMed  Google Scholar 

  181. 181.

    Foster, J. M., Carmines, P. K. & Pollock, J. S. PP2B-dependent NO production in the medullary thick ascending limb during diabetes. Am. J. Physiol. Renal Physiol. 297, F471–F480 (2009).

    CAS  PubMed  Google Scholar 

  182. 182.

    Pollock, C. A., Lawrence, J. R. & Field, M. J. Tubular sodium handling and tubuloglomerular feedback in experimental diabetes mellitus. Am. J. Physiol. 260, F946–F952 (1991).

    CAS  PubMed  Google Scholar 

  183. 183.

    Zhang, J. et al. Macula densa SGLT1-NOS1-tubuloglomerular feedback pathway, a new mechanism for glomerular hyperfiltration during hyperglycemia. J. Am. Soc. Nephrol. 30, 578–593 (2019).

    PubMed  Google Scholar 

  184. 184.

    Sipos, A., Vargas, S. & Peti-Peterdi, J. Direct demonstration of tubular fluid flow sensing by macula densa cells. Am. J. Physiol. Renal Physiol. 299, F1087–F1093 (2010).

    CAS  PubMed  Google Scholar 

  185. 185.

    Lenihan, C. R. et al. Longitudinal study of living kidney donor glomerular dynamics after nephrectomy. J. Clin. Invest. 125, 1311–1318 (2015).

    PubMed  Google Scholar 

  186. 186.

    Shirley, D. G. & Walter, S. J. Acute and chronic changes in renal function following unilateral nephrectomy. Kidney Int. 40, 62–68 (1991).

    CAS  PubMed  Google Scholar 

  187. 187.

    Ott, M., Forssén, B. & Werneke, U. Lithium treatment, nephrogenic diabetes insipidus and the risk of hypernatraemia: a retrospective cohort study. Ther. Adv. Psychopharmacol. 9, 2045125319836563 (2019).

    PubMed  Google Scholar 

  188. 188.

    Bockenhauer, D. & Bichet, D. G. Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus. Nat. Rev. Nephrol. 11, 576–588 (2015).

    CAS  PubMed  Google Scholar 

  189. 189.

    Upsdell, S. M., Leeson, S. M., Brooman, P. J. & O’Reilly, P. H. Diuretic-induced urinary flow rates at varying clearances and their relevance to the performance and interpretation of diuresis renography. Br. J. Urol. 61, 14–18 (1988).

    CAS  PubMed  Google Scholar 

  190. 190.

    Reyes, A. J. Effects of diuretics on outputs and flows of urine and urinary solutes in healthy subjects. Drugs 41, 35–59 (1991).

    CAS  PubMed  Google Scholar 

  191. 191.

    Gurevitch, E. J., Kella, N., Gapin, T. & Roehrborn, C. G. Urinary flow rate recording: the impact of a single dose of a diuretic on clinic logistics and flow rate parameters. J. Urol. 161, 1509–1512 (1999).

    CAS  PubMed  Google Scholar 

  192. 192.

    Arampatzis, S. et al. Impact of diuretic therapy-associated electrolyte disorders present on admission to the emergency department: a cross-sectional analysis. BMC Med. 11, 83 (2013).

    PubMed  Google Scholar 

  193. 193.

    Clayton, J. A., Rodgers, S., Blakey, J., Avery, A. & Hall, I. P. Thiazide diuretic prescription and electrolyte abnormalities in primary care. Br. J. Clin. Pharmacol. 61, 87–95 (2006).

    CAS  PubMed  Google Scholar 

  194. 194.

    Helal, I. et al. Glomerular hyperfiltration and renal progression in children with autosomal dominant polycystic kidney disease. Clin. J. Am. Soc. Nephrol. 6, 2439–2443 (2011).

    PubMed  Google Scholar 

  195. 195.

    Rule, A. D. et al. Characteristics of renal cystic and solid lesions based on contrast-enhanced computed tomography of potential kidney donors. Am. J. Kidney Dis. 59, 611–618 (2012).

    PubMed  Google Scholar 

  196. 196.

    Gimpel, C. et al. Imaging of kidney cysts and cystic kidney diseases in children: an international working group consensus statement. Radiology 290, 769–782 (2019).

    PubMed  Google Scholar 

  197. 197.

    Ong, A. C. M., Devuyst, O., Knebelmann, B. & Walz, G. ERA-EDTA Working Group for inherited kidney diseases. Autosomal dominant polycystic kidney disease: the changing face of clinical management. Lancet 385, 1993–2002 (2015).

    PubMed  Google Scholar 

  198. 198.

    Nauli, S. M. et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 33, 129–137 (2003).

    CAS  PubMed  Google Scholar 

  199. 199.

    Chebib, F. T., Sussman, C. R., Wang, X., Harris, P. C. & Torres, V. E. Vasopressin and disruption of calcium signalling in polycystic kidney disease. Nat. Rev. Nephrol. 11, 451–464 (2015).

    CAS  PubMed  Google Scholar 

  200. 200.

    Wilson, P. D., Hovater, J. S., Casey, C. C., Fortenberry, J. A. & Schwiebert, E. M. ATP release mechanisms in primary cultures of epithelia derived from the cysts of polycystic kidneys. J. Am. Soc. Nephrol. 10, 218–229 (1999).

    CAS  PubMed  Google Scholar 

  201. 201.

    Schwiebert, E. M. et al. Autocrine extracellular purinergic signaling in epithelial cells derived from polycystic kidneys. Am. J. Physiol. Renal Physiol. 282, F763–F775 (2002).

    CAS  PubMed  Google Scholar 

  202. 202.

    Chang, M.-Y. et al. Inhibition of the P2X7 receptor reduces cystogenesis in PKD. J. Am. Soc. Nephrol. 22, 1696–1706 (2011).

    CAS  PubMed  Google Scholar 

  203. 203.

    Palygin, O. et al. Characterization of purinergic receptor expression in ARPKD cystic epithelia. Purinergic Signal. 2, 40–13 (2018).

    Google Scholar 

  204. 204.

    Arkhipov, S. N. & Pavlov, T. S. ATP release into ADPKD cysts via pannexin-1/P2X7 channels decreases ENaC activity. Biochem. Biophys. Res. Commun. 513, 166–171 (2019).

    CAS  PubMed  Google Scholar 

  205. 205.

    Verschuren, E. H. J. et al. Polycystin-1 dysfunction impairs electrolyte and water handling in a renal precystic mouse model for ADPKD. Am. J. Physiol. Renal Physiol. 315, F537–F546 (2018).

    CAS  PubMed  Google Scholar 

  206. 206.

    Ahrabi, A. K. et al. PKD1 haploinsufficiency causes a syndrome of inappropriate antidiuresis in mice. J. Am. Soc. Nephrol. 18, 1740–1753 (2007).

    CAS  PubMed  Google Scholar 

  207. 207.

    Bastos, A. P. et al. Pkd1 haploinsufficiency increases renal damage and induces microcyst formation following ischemia/reperfusion. J. Am. Soc. Nephrol. 20, 2389–2402 (2009).

    CAS  PubMed  Google Scholar 

  208. 208.

    Nishiura, J. L. et al. Evaluation of nephrolithiasis in autosomal dominant polycystic kidney disease patients. Clin. J. Am. Soc. Nephrol. 4, 838–844 (2009).

    CAS  PubMed  Google Scholar 

  209. 209.

    Pavik, I. et al. Patients with autosomal dominant polycystic kidney disease have elevated fibroblast growth factor 23 levels and a renal leak of phosphate. Kidney Int. 79, 234–240 (2011).

    CAS  PubMed  Google Scholar 

  210. 210.

    Pietrzak-Nowacka, M. et al. Calcium-phosphate metabolism parameters and erythrocyte Ca(2+) concentration in autosomal dominant polycystic kidney disease patients with normal renal function. Arch. Med. Sci. 9, 837–842 (2013).

    CAS  PubMed  Google Scholar 

  211. 211.

    Pietrzak-Nowacka, M. et al. Association of kidney and cysts dimensions with anthropometric and biochemical parameters in patients with ADPKD. Ren. Fail. 37, 798–803 (2015).

    CAS  PubMed  Google Scholar 

  212. 212.

    Essig, M. & Friedlander, G. Tubular shear stress and phenotype of renal proximal tubular cells. J. Am. Soc. Nephrol. 14, S33–S35 (2003).

    PubMed  Google Scholar 

  213. 213.

    Dardik, A. et al. Differential effects of orbital and laminar shear stress on endothelial cells. J. Vasc. Surg. 41, 869–880 (2005).

    PubMed  Google Scholar 

  214. 214.

    Davies, P. F., Remuzzi, A., Gordon, E. J., Dewey, C. F. & Gimbrone, M. A. Turbulent fluid shear stress induces vascular endothelial cell turnover in vitro. Proc. Natl Acad. Sci. USA 83, 2114–2117 (1986).

    CAS  PubMed  Google Scholar 

  215. 215.

    Davies, P. F. How do vascular endothelial cells respond to flow? Physiology 4, 22–25 (1989).

    Google Scholar 

  216. 216.

    Revell, D. Z. & Yoder, B. K. Intravital visualization of the primary cilium, tubule flow, and innate immune cells in the kidney utilizing an abdominal window imaging approach. Methods Cell Biol. 154, 67–83 (2019).

    PubMed  Google Scholar 

  217. 217.

    Ryu, H. & Layton, A. T. Tubular fluid flow and distal NaCl delivery mediated by tubuloglomerular feedback in the rat kidney. J. Math. Biol. 68, 1023–1049 (2014).

    PubMed  Google Scholar 

  218. 218.

    Steinhausen, M. & Tanner, G. A. in Microcirculation and tubular urine flow in the mammalian kidney cortex (in vivo microscopy) (Springer, 1976).

  219. 219.

    Forbes, T. A. et al. Patient-iPSC-derived kidney organoids show functional validation of a ciliopathic renal phenotype and reveal underlying pathogenetic mechanisms. Am. J. Hum. Genet. 102, 816–831 (2018).

    CAS  PubMed  Google Scholar 

  220. 220.

    Homan, K. A. et al. Bioprinting of 3D convoluted renal proximal tubules on perfusable chips. Sci. Rep. 6, 34845 (2016).

    CAS  PubMed  Google Scholar 

  221. 221.

    Lin, N. Y. C. et al. Renal reabsorption in 3D vascularized proximal tubule models. Proc. Natl Acad. Sci. USA 116, 5399–5404 (2019).

    CAS  PubMed  Google Scholar 

  222. 222.

    Morizane, R. & Bonventre, J. V. Kidney organoids: a translational journey. Trends Mol. Med. 23, 246–263 (2017).

    PubMed  Google Scholar 

  223. 223.

    Wilmer, M. J. et al. Kidney-on-a-chip technology for drug-induced nephrotoxicity screening. Trends Biotechnol. 34, 156–170 (2016).

    CAS  PubMed  Google Scholar 

  224. 224.

    Homan, K. A. et al. Flow-enhanced vascularization and maturation of kidney organoids in vitro. Nat. Methods 16, 255–262 (2019).

    CAS  PubMed  Google Scholar 

  225. 225.

    Brenner, B. M., Deen, W. M. & Robertson, C. R. Determinants of glomerular filtration rate. Annu. Rev. Physiol. 38, 11–19 (1976).

    CAS  PubMed  Google Scholar 

  226. 226.

    Tucker, B. J. & Blantz, R. C. An analysis of the determinants of nephron filtration rate. Am. J. Physiol. 232, F477–F483 (1977).

    CAS  PubMed  Google Scholar 

  227. 227.

    Singh, P. & Thomson, S. C. Renal homeostasis and tubuloglomerular feedback. Curr. Opin. Nephrol. Hypertens. 19, 59–64 (2010).

    PubMed  Google Scholar 

  228. 228.

    Navar, L. G. Intrarenal renin-angiotensin system in regulation of glomerular function. Curr. Opin. Nephrol. Hypertens. 23, 38–45 (2014).

    CAS  PubMed  Google Scholar 

  229. 229.

    Romero, C. A. & Carretero, O. A. Tubule-vascular feedback in renal autoregulation. Am. J. Physiol. Renal Physiol. 316, F1218–F1226 (2019).

    CAS  PubMed  Google Scholar 

  230. 230.

    Hansen, P. B. & Schnermann, J. Vasoconstrictor and vasodilator effects of adenosine in the kidney. Am. J. Physiol. Renal Physiol. 285, F590–F599 (2003).

    CAS  PubMed  Google Scholar 

  231. 231.

    Satir, P., Pedersen, L. B. & Christensen, S. T. The primary cilium at a glance. J. Cell. Sci. 123, 499–503 (2010).

    CAS  PubMed  Google Scholar 

  232. 232.

    Satir, P. & Christensen, S. T. Overview of structure and function of mammalian cilia. Annu. Rev. Physiol. 69, 377–400 (2007).

    CAS  PubMed  Google Scholar 

  233. 233.

    Praetorius, H. A. & Spring, K. R. Bending the MDCK cell primary cilium increases intracellular calcium. J. Membr. Biol. 184, 71–79 (2001).

    CAS  PubMed  Google Scholar 

  234. 234.

    Praetorius, H. A. & Spring, K. R. Removal of the MDCK cell primary cilium abolishes flow sensing. J. Membr. Biol. 191, 69–76 (2003).

    CAS  PubMed  Google Scholar 

  235. 235.

    Liu, W. et al. Mechanoregulation of intracellular Ca2+ concentration is attenuated in collecting duct of monocilium-impaired orpk mice. Am. J. Physiol. Renal Physiol. 289, F978–F988 (2005).

    CAS  PubMed  Google Scholar 

  236. 236.

    Pala, R., Alomari, N. & Nauli, S. M. Primary cilium-dependent signaling mechanisms. Int. J. Mol. Sci. 18, 2272 (2017).

    Google Scholar 

  237. 237.

    Sun, S., Fisher, R. L., Bowser, S. S., Pentecost, B. T. & Sui, H. Three-dimensional architecture of epithelial primary cilia. Proc. Natl Acad. Sci. USA 116, 9370–9379 (2019).

    CAS  PubMed  Google Scholar 

  238. 238.

    Wood, C. R. & Rosenbaum, J. L. Ciliary ectosomes: transmissions from the cell’s antenna. Trends Cell Biol. 25, 276–285 (2015).

    CAS  PubMed  Google Scholar 

  239. 239.

    Anyatonwu, G. I., Estrada, M., Tian, X., Somlo, S. & Ehrlich, B. E. Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2. Proc. Natl Acad. Sci. USA 104, 6454–6459 (2007).

    CAS  PubMed  Google Scholar 

  240. 240.

    Ortiz, P. A., Hong, N. J. & Garvin, J. L. Luminal flow induces eNOS activation and translocation in the rat thick ascending limb. Am. J. Physiol. Renal Physiol. 287, F274–F280 (2004).

    CAS  PubMed  Google Scholar 

Download references


The work of the authors is supported by grants from the Dutch Kidney Foundation (15OP03) to R.J.M.B. and D.J.M.P., and from the Netherlands Organization for Scientific Research (NWO VICI 016.130.668) to J.G.J.H.

Author information




All authors contributed to researching of data for the article, discussed its content, wrote and reviewed the text and edited the manuscript before submission.

Corresponding author

Correspondence to Joost G. J. Hoenderop.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Nephrology thanks Matthew Bailey, Alexander Staruschenko and Alan Weinstein for their contribution to the peer-review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Tubuloglomerular feedback

Feedback mechanism to regulate glomerular filtration rate involving the macula densa.


Response mechanism to mechanical stimuli.

Fluid shear stress

Measure of the resistance to fluid movement, related to the fluid viscosity.

Circumferential stretch

Stretch of renal epithelial cells lining the tubular lumen.


Plasma membrane extensions that increase the surface area.

Primary cilium

Single non-motile cilium that lacks a central pair of microtubules.

Autocrine activation

Signalling mechanism in which a secreted molecule of a cell binds to a receptor on that same cell.

Paracrine activation

Signalling mechanism in which a secreted molecule of a cell binds to a receptor on another cell.

G protein-coupled receptors

Protein family of receptors capable of detecting molecules extracellularly and in turn activating signalling pathways intracellularly.


Technique to study tubular cell function in perfused isolated renal tubules.


Technique to study single nephron function in the intact kidney.

Patch clamp technique

Technique in electrophysiology to study ion channel characteristics in isolated living cells.


Technique that mimics, in miniature scale, the behaviour of fluids in order to study the effect of fluid flow on a target tissue; this technique is especially applied in organ-on-a-chip technology.

Oscillatory turbulent flow

Flow of fluid in an irregular motion in both direction and magnitude.

Unidirectional laminar flow

Flow of fluid in a regular motion with a constant direction.


Miniaturized versions of an organ, produced in vitro in 3D.

Kidney-on-a-chip technology

In vitro system mimicking the 3D microenvironment of the kidney.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Verschuren, E.H.J., Castenmiller, C., Peters, D.J.M. et al. Sensing of tubular flow and renal electrolyte transport. Nat Rev Nephrol 16, 337–351 (2020).

Download citation