A Novel Mechanism of Renal Microcirculation Regulation: Connecting Tubule-Glomerular Feedback

  • Cesar A. RomeroEmail author
  • Oscar A. Carretero
Mechanisms of Hypertension and Target-Organ Damage (Matthew Weir, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Mechanisms of Hypertension and Target-Organ Damage


Purpose of Review

In this review, we summarized the current knowledge of connecting tubule-glomerular feedback (CTGF), a novel mechanism of renal microcirculation regulation that integrates sodium handling in the connecting tubule (CNT) with kidney hemodynamics.

Recent Findings

Connecting tubule-glomerular feedback is a crosstalk communication between the CNT and the afferent arteriole (Af-Art), initiated by sodium chloride through the epithelial sodium channel (ENaC). High sodium in the CNT induces Af-Art vasodilation, increasing glomerular pressure and the glomerular filtration rate and favoring sodium excretion. CTGF antagonized and reset tubuloglomerular feedback and thus increased sodium excretion. CTGF is absent in spontaneous hypertensive rats and is overactivated in Dahl salt-sensitive rats. CTGF is also modulated by angiotensin II and aldosterone.


CTGF is a feedback mechanism that integrates sodium handling in the CNT with glomerular hemodynamics. Lack of CTGF could promote hypertension, and CTGF overactivation may favor glomerular damage and proteinuria. More studies are needed to explore the alterations in renal microcirculation and the role of these alterations in the genesis of hypertension and glomerular damage in animals and humans.

Key Points

CTGF is a vasodilator mechanism that regulates afferent arteriole resistance.

CTGF is absent in spontaneous hypertensive rats and overactivated in Dahl salt-sensitive rats.

CTGF in excess may promote glomerular damage and proteinuria, while the absence may participate in sodium retention and hypertension.


Connecting tubule-glomerular feedback Tubuloglomerular feedback ENaC Hypertension Proteinuria 



We would like to thank Dr. Tengis Pavlov for the assistance in the figure preparation.


This study was funded by the Heart, Lung, and Blood Institute of the National Institutes of Health under award number HL-028982. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Guyton AC. Blood pressure control—special role of the kidneys and body fluids. Science (New York, NY). 1991;252(5014):1813–6.CrossRefGoogle Scholar
  2. 2.
    Frame AA, Wainford RD. Renal sodium handling and sodium sensitivity. Kidney Res Clin Pract. 2017;36(2):117–31.CrossRefGoogle Scholar
  3. 3.
    Neal CR, Arkill K, Bell JS, Betteridge KB, Bates DO, Winlove CP, et al. Novel haemodynamic structures in the human glomerulus. Am J Physiol Ren Physiol. 2018;315:F1370–84. Scholar
  4. 4.
    Brenner BM, Troy JL, Daugharty TM. The dynamics of glomerular ultrafiltration in the rat. J Clin Investig. 1971;50:1776–80.CrossRefGoogle Scholar
  5. 5.
    Deen WM, Robertson CR, Brenner BM. Glomerular ultrafiltration. FedProc. 1974;33:14–20.Google Scholar
  6. 6.
    Brenner BM, Troy JL, Daugharty TM, Deen WM, Robertson CR. Dynamics of glomerular ultrafiltration in the rat. II. Plasma-flow dependence of GFR. Am J Physiol. 1972;223:1184–90.PubMedGoogle Scholar
  7. 7.
    •• Carlstrom M, Wilcox CS, Arendshorst WJ. Renal autoregulation in health and disease. Physiol Rev. 2015;95(2):405–511 This is an extensive review that describe the renal autoregulation mechanisms with very precised details. CrossRefGoogle Scholar
  8. 8.
    • Ren Y, Garvin JL, Liu R, Carretero OA. Crosstalk between the connecting tubule and the afferent arteriole regulates renal microcirculation. Kidney Int. 2007;71(11):1116–21 This is the first description of CTGF. CrossRefGoogle Scholar
  9. 9.
    Peti-Peterdi J, Bebok Z, Lapointe JY, Bell PD. Novel regulation of cell [Na(+)] in macula densa cells: apical Na(+) recycling by H-K-ATPase. Am J Physiol Ren Physiol. 2002;282(2):F324–9.CrossRefGoogle Scholar
  10. 10.
    Komlosi P, Peti-Peterdi J, Fuson AL, Fintha A, Rosivall L, Bell PD. Macula densa basolateral ATP release is regulated by luminal [NaCl] and dietary salt intake. Am J Physiol Ren Physiol. 2004;286:F1054–F8.CrossRefGoogle Scholar
  11. 11.
    Ren Y, Garvin JL, Liu R, Carretero OA. Role of macula densa adenosine triphosphate (ATP) in tubuloglomerular feedback. Kidney Int. 2004;66(4):1479–85.CrossRefGoogle Scholar
  12. 12.
    Kirk KL, Bell PD, Barfuss DW, Ribadeneira M. Direct visualization of the isolated and perfused macula densa. Am J Physiol. 1985;248:F890–F4.PubMedGoogle Scholar
  13. 13.
    Barajas L, Powers K, Carretero OA, Scicli AG, Inagami T. Immunocytochemical localization of renin and kallikrein in the rat renal cortex. Kidney Int. 1986;29(5):965–70.CrossRefGoogle Scholar
  14. 14.
    Dorup J, Morsing P, Rasch R. Tubule-tubule and tubule-arteriole contacts in rat kidney distal nephrons. A morphologic study based on computer-assisted three-dimensional reconstructions. Lab Investig. 1992;67(6):761–9.PubMedGoogle Scholar
  15. 15.
    Loffing J, Korbmacher C. Regulated sodium transport in the renal connecting tubule (CNT) via the epithelial sodium channel (ENaC). Pflugers Arch Eur J Physiol. 2009;458(1):111–35.CrossRefGoogle Scholar
  16. 16.
    Frindt G, Palmer LG. Na channels in the rat connecting tubule. Am J Physiol Ren Physiol. 2004;286(4):F669–74.CrossRefGoogle Scholar
  17. 17.
    Wall SM, Lazo-Fernandez Y. The role of pendrin in renal physiology. Annu Rev Physiol. 2015;77:363–78.CrossRefGoogle Scholar
  18. 18.
    Jacques T, Picard N, Miller RL, Riemondy KA, Houillier P, Sohet F, et al. Overexpression of pendrin in intercalated cells produces chloride-sensitive hypertension. J Am Soc Nephrol. 2013;24(7):1104–13.CrossRefGoogle Scholar
  19. 19.
    Wall SM. Renal intercalated cells and blood pressure regulation. Kidney Res Clin Pract. 2017;36(4):305–17.CrossRefGoogle Scholar
  20. 20.
    • Liu R, Layton AT. Modeling the effects of positive and negative feedback in kidney blood flow control. Math Biosci. 2016;276:8–18 This study explore the effects of CTGF on TGF. CrossRefGoogle Scholar
  21. 21.
    Sun D, Samuelson LC, Yang T, Huang Y, Paliege A, Saunders T, et al. Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine 1 receptors. Proc Natl Acad Sci U S A. 2001;98:9983–8.CrossRefGoogle Scholar
  22. 22.
    Ren Y, D’Ambrosio MA, Garvin JL, Wang H, Carretero OA. Possible mediators of connecting tubule glomerular feedback. Hypertension. 2009;53(part 2):319–23.CrossRefGoogle Scholar
  23. 23.
    Ren Y, D’Ambrosio MA, Wang H, Garvin JL, Carretero OA. Participation of prostaglandin E 2 and EP4 receptors in connecting tubule glomerular feedback (CTGF) [abstract]. Hypertension. 2012;60(3 Supplement):A33.Google Scholar
  24. 24.
    Ren Y, D’Ambrosio MA, Wang H, Peterson EL, Garvin JL, Carretero OA. Mechanisms of angiotensin II-enhanced connecting tubule glomerular feedback. Am J Physiol Ren Physiol. 2012;303(2):F259–F65.CrossRefGoogle Scholar
  25. 25.
    Ren Y, D’Ambrosio MA, Garvin JL, Leung P, Kutskill K, Wang H, et al. Aldosterone sensitizes connecting tubule glomerular feedback via the aldosterone receptor GPR30. Am J Physiol Ren Physiol. 2014;307(4):F427–34.CrossRefGoogle Scholar
  26. 26.
    Romero CA, Peixoto AJ, Orias M. Estimated GFR or albuminuria: which one is really associated with resistant hypertension? Semin Nephrol. 2014;34(5):492–7.CrossRefGoogle Scholar
  27. 27.
    Brown R, Ollerstam A, Persson AE. Neuronal nitric oxide synthase inhibition sensitizes the tubuloglomerular feedback mechanism after volume expansion. Kidney Int. 2004;65(4):1349–56.CrossRefGoogle Scholar
  28. 28.
    Wang H, D’Ambrosio MA, Garvin JL, Ren Y, Carretero OA. Connecting tubule glomerular feedback in hypertension. Hypertension. 2013;62(4):738–45.CrossRefGoogle Scholar
  29. 29.
    Monu SR, Ren Y, Masjoan-Juncos JX, Kutskill K, Wang H, Kumar N, et al. Connecting tubule glomerular feedback mediates tubuloglomerular feedback resetting after unilateral nephrectomy. Am J Physiol Ren Physiol. 2018;315(4):F806–F11.CrossRefGoogle Scholar
  30. 30.
    Frohlich ED, Messerli FH, Dunn FG, Oigman W, Ventura HO, Sundgaard-Riise K. Greater renal vascular involvement in the black patient with essential hypertension. A comparison of systemic and renal hemodynamics in black and white patients. Miner Electrolyte Metab. 1984;10(3):173–7.PubMedGoogle Scholar
  31. 31.
    Weir MR. Salt intake and hypertensive renal injury in African-Americans. A therapeutic perspective. Am J Hypertens. 1995;8(6):635–44.CrossRefGoogle Scholar
  32. 32.
    Raij L, Azar S, Keane WF. Role of hypertension in progressive glomerular immune injury. Hypertension. 1985;7(3 Pt 1):398–404.CrossRefGoogle Scholar
  33. 33.
    Pavlov TS, Staruschenko A. Involvement of ENaC in the development of salt-sensitive hypertension. Am J Physiol Ren Physiol. 2017;313(2):F135–F40.CrossRefGoogle Scholar
  34. 34.
    Wang H, Romero CA, Masjoan Juncos JX, Monu SR, Peterson EL, Carretero OA. Effect of salt intake on afferent arteriolar dilatation: role of connecting tubule glomerular feedback (CTGF). Am J Physiol Ren Physiol. 2017;313(6):F1209–F15.CrossRefGoogle Scholar
  35. 35.
    Holstein-Rathlou NH, Leyssac PP. TGF-mediated oscillations in the proximal intratubular pressure: differences between spontaneously hypertensive rats and Wistar-Kyoto rats. Acta Physiol Scand. 1986;126(3):333–9.CrossRefGoogle Scholar
  36. 36.
    Bianchi G, Fox U, Di Francesco GF, Giovanetti AM, Pagetti D. Blood pressure changes produced by kidney cross-transplantation between spontaneously hypertensive rats and normotensive rats. Clin Sci Mol Med. 1974;47(5):435–48.PubMedGoogle Scholar
  37. 37.
    Song J, Wang L, Fan F, Wei J, Zhang J, Lu Y, et al. Role of the primary cilia on the macula Densa and thick ascending limbs in regulation of sodium excretion and hemodynamics. Hypertension. 2017;70(2):324–33.CrossRefGoogle Scholar
  38. 38.
    Lu Y, Wei J, Stec DE, Roman RJ, Ge Y, Cheng L, et al. Macula Densa nitric oxide synthase 1beta protects against salt-sensitive hypertension. J Am Soc Nephrol. 2016;27(8):2346–56.CrossRefGoogle Scholar
  39. 39.
    Romero CA, Monu S, Knight R, Carretero OA, editors. Connecting tubule-glomerular feedback (CTGF) in renal hemodynamics and blood pressure (BP) after unilateral nephrectomy (UNX). Hypertension; 2016: Vol 68, Issue Suppl_1 (Abstract P148), USA.Google Scholar
  40. 40.
    Stevens PE, Levin A. Kidney disease: improving global outcomes chronic kidney disease guideline development work group M. evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158(11):825–30.CrossRefGoogle Scholar
  41. 41.
    Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD. Obesity-related glomerulopathy: an emerging epidemic. Kidney Int. 2001;59(4):1498–509.CrossRefGoogle Scholar
  42. 42.
    Praga M, Morales E. The fatty kidney: obesity and renal disease. Nephron. 2017;136(4):273–6.CrossRefGoogle Scholar
  43. 43.
    Maheshwari M, Romero CA, Monu SR, Kumar N, Liao TD, Peterson EL, et al. Renal protective effects of N-acetyl-Seryl-aspartyl-Lysyl-proline (ac-SDKP) in obese rats on a high-salt diet. Am J Hypertens. 2018;31(8):902–9.CrossRefGoogle Scholar
  44. 44.
    Chagnac A, Herman M, Zingerman B, Erman A, Rozen-Zvi B, Hirsh J, et al. Obesity-induced glomerular hyperfiltration: its involvement in the pathogenesis of tubular sodium reabsorption. Nephrol Dial Transplant. 2008;23(12):3946–52.CrossRefGoogle Scholar
  45. 45.
    Monu SR, Maheshwari M, Peterson EL, Carretero OA. Role of connecting tubule glomerular feedback in obesity related renal damage. Am J Physiol Ren Physiol. 2018.
  46. 46.
    Andersen H, Hansen PB, Bistrup C, Nielsen F, Henriksen JE, Jensen BL. Significant natriuretic and antihypertensive action of the epithelial sodium channel blocker amiloride in diabetic patients with and without nephropathy. J Hypertens. 2016;34(8):1621–9.CrossRefGoogle Scholar
  47. 47.
    Williams B, MacDonald TM, Morant SV, Webb DJ, Sever P, McInnes GT, et al. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. Lancet Diabetes Endocrinol. 2018;6(6):464–75.CrossRefGoogle Scholar
  48. 48.
    Viera AJ, Wouk N. Potassium disorders: hypokalemia and hyperkalemia. Am Fam Phys. 2015;92(6).Google Scholar
  49. 49.
    Sepehrdad R, Chander PN, Oruene A, Rosenfeld L, Levine S, Stier CT Jr. Amiloride reduces stroke and renalinjury in stroke-prone hypertensive rats. Am J Hypertens. 2003;16(4):312–8.CrossRefGoogle Scholar
  50. 50.
    Zhang B, Xie S, Shi W, Yang Y. Amiloride off-target effect inhibits podocyte urokinase receptor expression and reduces proteinuria. Nephrol Dial Transplant. 2012;27(5):1746–55.CrossRefGoogle Scholar
  51. 51.
    Xu LB, Chi N, Shi W. Amiloride, a urokinase-type plasminogen activator receptor (uTPA) inhibitor, reduces proteinurea in podocytes. Genet Mol Res. 2015;14(3):9518–29.CrossRefGoogle Scholar
  52. 52.
    Vassalli JD, Belin D. Amiloride selectively inhibits the urokinase-type plasminogen activator. FEBS Lett. 1987;214(1):187–91.CrossRefGoogle Scholar
  53. 53.
    Svenningsen P, Andersen H, Nielsen LH, Jensen BL. Urinary serine proteases and activation of ENaC in kidney—implications for physiological renal salt handling and hypertensive disorders with albuminuria. Pflugers Arch Eur J Physiol. 2015;467(3):531–42.CrossRefGoogle Scholar
  54. 54.
    Staehr M, Buhl KB, Andersen RF, Svenningsen P, Nielsen F, Hinrichs GR, et al. Aberrant glomerular filtration of urokinase-type plasminogen activator in nephrotic syndrome leads to amiloride-sensitive plasminogen activation in urine. Am J Physiol Ren Physiol. 2015;309(3):F235–41.CrossRefGoogle Scholar
  55. 55.
    Trimarchi H, Forrester M, Lombi F, Pomeranz V, Rana MS, Karl A, et al. Amiloride as an alternate adjuvant antiproteinuric agent in Fabry disease: the potential roles of plasmin and uPAR. Case Rep Nephrol. 2014;2014:854521.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Buhl KB, Oxlund CS, Friis UG, Svenningsen P, Bistrup C, Jacobsen IA, et al. Plasmin in urine from patients with type 2 diabetes and treatment-resistant hypertension activates ENaC in vitro. J Hypertens. 2014;32(8):1672–7 discussion 7.CrossRefGoogle Scholar
  57. 57.
    Oxlund CS, Buhl KB, Jacobsen IA, Hansen MR, Gram J, Henriksen JE, et al. Amiloride lowers blood pressure and attenuates urine plasminogen activation in patients with treatment-resistant hypertension. J Am Soc Hypertens. 2014;8(12):872–81.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Hypertension and Vascular Research Division, Department of Internal MedicineHenry Ford HospitalDetroitUSA

Personalised recommendations