Abstract
Renin synthesis and renin secretion at the level of renal juxtaglomerular cells are regulated by neurotransmitters, hormones, paracrine, and mechanical signals. Although morphological evidence has indicated an intense intercellular communication of renin cells via connexins between the cells composing the juxtaglomerlar area, the functional behavior of renin-secreting cells has been considered of that of individual isolated cells for a long time. Findings obtained during recent years shed first light on the functional relevance of connexins for the control of renin secretion and also for the positioning of renin-secreting cells in the kidney. This short review aims to summarize these findings and tries to set them into a functional context.
Similar content being viewed by others
References
Alonso F, Boittin FX, Beny JL, Haefliger JA (2010) Loss of connexin40 is associated with decreased endothelium-dependent relaxations and eNOS levels in the mouse aorta. Am J Physiol Heart Circ Physiol 299:H1365–1373
Arensbak B, Mikkelsen HB, Gustafsson F, Christensen T, Holstein-Rathlou NH (2001) Expression of connexin 37, 40, and 43 mRNA and protein in renal preglomerular arterioles. Histochem Cell Biol 115:479–487
Baek EB, Kim SJ (2011) Mechanisms of myogenic response: Ca(2+)-dependent and -independent signaling. J Smooth Muscle Res 47:55–65
Barajas L, Liu L, Tucker M (1994) Localization of connexin43 in rat kidney. Kidney Int 46:621–626
Barrio LC, Capel J, Jarillo JA, Castro C, Revilla A (1997) Species-specific voltage-gating properties of connexin-45 junctions expressed in Xenopus oocytes. Biophys J 73:757–769
Beblo DA, Wang HZ, Beyer EC, Westphale EM, Veenstra RD (1995) Unique conductance, gating, and selective permeability properties of gap junction channels formed by connexin40. Circ Res 77:813–822
Bukauskas FF, Elfgang C, Willecke K, Weingart R (1995) Biophysical properties of gap junction channels formed by mouse connexin40 in induced pairs of transfected human HeLa cells. Biophys J 68:2289–2298
Castrop H, Hocherl K, Kurtz A, Schweda F, Todorov V, Wagner C (2010) Physiology of kidney renin. Physiol Rev 90:607–673
Davis JO, Freeman RH (1976) Mechanisms regulating renin release. Physiol Rev 56:1–56
De Vriese AS, Van de Voorde J, Lameire NH (2002) Effects of connexin-mimetic peptides on nitric oxide synthase- and cyclooxygenase-independent renal vasodilation. Kidney Int 61:177–185
de Wit C, Roos F, Bolz SS, Kirchhoff S, Kruger O, Willecke K, Pohl U (2000) Impaired conduction of vasodilation along arterioles in connexin40-deficient mice. Circ Res 86:649–655
de Wit C, Roos F, Bolz SS, Pohl U (2003) Lack of vascular connexin 40 is associated with hypertension and irregular arteriolar vasomotion. Physiol Genomics 13:169–177
Evans WH, De Vuyst E, Leybaert L (2006) The gap junction cellular internet: connexin hemichannels enter the signalling limelight. Biochem J 397:1–14
Figueroa XF, Duling BR (2008) Dissection of two Cx37-independent conducted vasodilator mechanisms by deletion of Cx40: electrotonic versus regenerative conduction. Am J Physiol Heart Circ Physiol 295:H2001–2007
Fray JC, Park CS (1986) Forskolin and calcium: interactions in the control of renin secretion and perfusate flow in the isolated rat kidney. J Physiol 375:361–375
Gollob MH (2006) Cardiac connexins as candidate genes for idiopathic atrial fibrillation. Curr Opin Cardiol 21:155–158
Haefliger JA, Demotz S, Braissant O, Suter E, Waeber B, Nicod P, Meda P (2001) Connexins 40 and 43 are differentially regulated within the kidneys of rats with renovascular hypertension. Kidney Int 60:190–201
Haefliger JA, Krattinger N, Martin D, Pedrazzini T, Capponi A, Doring B, Plum A, Charollais A, Willecke K, Meda P (2006) Connexin43-dependent mechanism modulates renin secretion and hypertension. J Clin Invest 116:405–413
Haefliger JA, Nicod P, Meda P (2004) Contribution of connexins to the function of the vascular wall. Cardiovasc Res 62:345–356
Hanner F, Sorensen CM, Holstein-Rathlou NH, Peti-Peterdi J (2010) Connexins and the kidney. Am J Physiol Regul Integr Comp Physiol 298:R1143–1155
Hanner F, von Maltzahn J, Maxeiner S, Toma I, Sipos A, Kruger O, Willecke K, Peti-Peterdi J (2008) Connexin45 is expressed in the juxtaglomerular apparatus and is involved in the regulation of renin secretion and blood pressure. Am J Physiol Regul Integr Comp Physiol 295:R371–380
Harris AL (2001) Emerging issues of connexin channels: biophysics fills the gap. Q Rev Biophys 34:325–472
Hellmann P, Winterhager E, Spray DC (1996) Properties of connexin40 gap junction channels endogenously expressed and exogenously overexpressed in human choriocarcinoma cell lines. Pflugers Arch 432:501–509
Hillis GS, Duthie LA, Mlynski R, McKay NG, Mistry S, MacLeod AM, Simpson JG, Haites NE (1997) The expression of connexin 43 in human kidney and cultured renal cells. Nephron 75:458–463
Hwan Seul K, Beyer EC (2000) Heterogeneous localization of connexin40 in the renal vasculature. Microvasc Res 59:140–148
Ichihara A, Suzuki H, Murakami M, Naitoh M, Matsumoto A, Saruta T (1995) Interactions between angiotensin II and norepinephrine on renin release by juxtaglomerular cells. Eur J Endocrinol 133:569–577
Imanishi M, Tsuji T, Nakamura S, Takamiya M (2001) Prostaglandin I(2)/E(2) ratios in unilateral renovascular hypertension of different severities. Hypertension 38:23–29
Krattinger N, Capponi A, Mazzolai L, Aubert JF, Caille D, Nicod P, Waeber G, Meda P, Haefliger JA (2007) Connexin40 regulates renin production and blood pressure. Kidney Int 72:814–822
Kruger O, Plum A, Kim JS, Winterhager E, Maxeiner S, Hallas G, Kirchhoff S, Traub O, Lamers WH, Willecke K (2000) Defective vascular development in connexin 45-deficient mice. Development 127:4179–4193
Kurt B, Kurtz L, Sequeira-Lopez ML, Gomez RA, Willecke K, Wagner C, Kurtz A (2011) Reciprocal expression of connexin 40 and 45 during phenotypical changes in renin-secreting cells. Am J Physiol Renal Physiol 300:F743–748
Kurtz A (2012) Renal connexins and blood pressure. Biochim Biophys Acta 1818(8):1903–1908
Kurtz A, Penner R (1989) Angiotensin II induces oscillations of intracellular calcium and blocks anomalous inward rectifying potassium current in mouse renal juxtaglomerular cells. Proc Natl Acad Sci U S A 86:3423–3427
Kurtz A, Pfeilschifter J, Hutter A, Buhrle C, Nobiling R, Taugner R, Hackenthal E, Bauer C (1986) Role of protein kinase C in inhibition of renin release caused by vasoconstrictors. Am J Physiol 250:C563–571
Kurtz L, Gerl M, Kriz W, Wagner C, Kurtz A (2009) Replacement of connexin 40 by connexin 45 causes ectopic localization of renin-producing cells in the kidney but maintains in vivo control of renin gene expression. Am J Physiol Renal Physiol 297:F403–409
Kurtz L, Janssen-Bienhold U, Kurtz A, Wagner C (2009) Connexin expression in renin-producing cells. J Am Soc Nephrol 20:506–512
Kurtz L, Madsen K, Kurt B, Jensen BL, Walter S, Banas B, Wagner C, and Kurtz A. High-level connexin expression in the human juxtaglomerular apparatus. Nephron Physiol 116: p1-8
Kurtz L, Schweda F, de Wit C, Kriz W, Witzgall R, Warth R, Sauter A, Kurtz A, Wagner C (2007) Lack of connexin 40 causes displacement of renin-producing cells from afferent arterioles to the extraglomerular mesangium. J Am Soc Nephrol 18:1103–1111
Lai EY, Wang Y, Persson AE, Manning RD Jr, Liu R (2011) Pressure induces intracellular calcium changes in juxtaglomerular cells in perfused afferent arterioles. Hypertens Res 34:942–948
Li A, Banerjee J, Leung CT, Peterson-Yantorno K, Stamer WD, Civan MM (2011) Mechanisms of ATP release, the enabling step in purinergic dynamics. Cell Physiol Biochem 28:1135–1144
Liao Y, Day KH, Damon DN, Duling BR (2001) Endothelial cell-specific knockout of connexin 43 causes hypotension and bradycardia in mice. Proc Natl Acad Sci U S A 98:9989–9994
Liu F, Arce FT, Ramachandran S, Lal R (2006) Nanomechanics of hemichannel conformations: connexin flexibility underlying channel opening and closing. J Biol Chem 281:23207–23217
Lubkemeier I, Machura K, Kurtz L, Neubauer B, Dobrowolski R, Schweda F, Wagner C, Willecke K, Kurtz A (2011) The connexin 40 A96S mutation causes renin-dependent hypertension. J Am Soc Nephrol 22:1031–1040
Moreno AP, Laing JG, Beyer EC, Spray DC (1995) Properties of gap junction channels formed of connexin 45 endogenously expressed in human hepatoma (SKHep1) cells. Am J Physiol 268:C356–365
Peti-Peterdi J (2006) Calcium wave of tubuloglomerular feedback. Am J Physiol Renal Physiol 291:F473–480
Ravier MA, Guldenagel M, Charollais A, Gjinovci A, Caille D, Sohl G, Wollheim CB, Willecke K, Henquin JC, Meda P (2005) Loss of connexin36 channels alters beta-cell coupling, islet synchronization of glucose-induced Ca2+ and insulin oscillations, and basal insulin release. Diabetes 54:1798–1807
Saez JC, Berthoud VM, Branes MC, Martinez AD, Beyer EC (2003) Plasma membrane channels formed by connexins: their regulation and functions. Physiol Rev 83:1359–1400
Saez JC, Connor JA, Spray DC, Bennett MV (1989) Hepatocyte gap junctions are permeable to the second messenger, inositol 1,4,5-trisphosphate, and to calcium ions. Proc Natl Acad Sci U S A 86:2708–2712
Sauter A, Machura K, Neubauer B, Kurtz A, Wagner C (2008) Development of renin expression in the mouse kidney. Kidney Int 73:43–51
Scholz H, Hamann M, Gotz KH, Kurtz A (1994) Role of calcium ions in the pressure control of renin secretion from the kidneys. Pflugers Arch 428:173–178
Schweda F, Kurtz L, de Wit C, Janssen-Bienhold U, Kurtz A, Wagner C (2009) Substitution of connexin40 with connexin45 prevents hyperreninemia and attenuates hypertension. Kidney Int 75:482–489
Schweda F, Riegger GA, Kurtz A, Kramer BK (2000) Store-operated calcium influx inhibits renin secretion. Am J Physiol Renal Physiol 279:F170–176
Sipos A, Vargas SL, Toma I, Hanner F, Willecke K, Peti-Peterdi J (2009) Connexin 30 deficiency impairs renal tubular ATP release and pressure natriuresis. J Am Soc Nephrol 20:1724–1732
Sorensen CM, and Holstein-Rathlou NH. Cell–cell communication in the kidney microcirculation. Microcirculation 2012
Spray DC, Stern JH, Harris AL, Bennett MV (1982) Gap junctional conductance: comparison of sensitivities to H and Ca ions. Proc Natl Acad Sci U S A 79:441–445
Takenaka T, Inoue T, Kanno Y, Okada H, Hill CE, Suzuki H (2008) Connexins 37 and 40 transduce purinergic signals mediating renal autoregulation. Am J Physiol Regul Integr Comp Physiol 294:R1–11
Takenaka T, Inoue T, Kanno Y, Okada H, Meaney KR, Hill CE, Suzuki H (2008) Expression and role of connexins in the rat renal vasculature. Kidney Int 73:415–422
Takenaka T, Inoue T, Okada H, Ohno Y, Miyazaki T, Chaston DJ, Hill CE, Suzuki H (2011) Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes. Diabetologia 54:2192–2201
Taugner R, Schiller A, Kaissling B, Kriz W (1978) Gap junctional coupling between the JGA and the glomerular tuft. Cell Tissue Res 186:279–285
Theis M, de Wit C, Schlaeger TM, Eckardt D, Kruger O, Doring B, Risau W, Deutsch U, Pohl U, Willecke K (2001) Endothelium-specific replacement of the connexin43 coding region by a lacZ reporter gene. Genesis 29:1–13
Toma I, Bansal E, Meer EJ, Kang JJ, Vargas SL, Peti-Peterdi J (2008) Connexin 40 and ATP-dependent intercellular calcium wave in renal glomerular endothelial cells. Am J Physiol Regul Integr Comp Physiol 294:R1769–1776
Van Dongen R, Peart WS (1974) Calcium dependence of the inhibitory effect of angiotensin on renin secretion in the isolated perfused kidney of the rat. Br J Pharmacol 50:125–129
van Veen TA, van Rijen HV, Jongsma HJ (2000) Electrical conductance of mouse connexin45 gap junction channels is modulated by phosphorylation. Cardiovasc Res 46:496–510
Wagner C (2008) Function of connexins in the renal circulation. Kidney Int 73:547–555
Wagner C, de Wit C, Kurtz L, Grunberger C, Kurtz A, Schweda F (2007) Connexin40 is essential for the pressure control of renin synthesis and secretion. Circ Res 100:556–563
Wagner C, Jobs A, Schweda F, Kurtz L, Kurt B, Lopez ML, Gomez RA, van Veen TA, de Wit C, Kurtz A (2010) Selective deletion of Connexin 40 in renin-producing cells impairs renal baroreceptor function and is associated with arterial hypertension. Kidney Int 78:762–768
Wagner C, Kurtz L, Schweda F, Simon AM, Kurtz A (2009) Connexin 37 is dispensable for the control of the renin system and for positioning of renin-producing cells in the kidney. Pflugers Arch 459:151–158
Yao J, Suwa M, Li B, Kawamura K, Morioka T, Oite T (2003) ATP-dependent mechanism for coordination of intercellular Ca2+ signaling and renin secretion in rat juxtaglomerular cells. Circ Res 93:338–345
Zhang J, Hill CE (2005) Differential connexin expression in preglomerular and postglomerular vasculature: accentuation during diabetes. Kidney Int 68:1171–1185
Acknowledgments
The authors’ work is financially supported by grants from the German Research Foundation (Sonderforschungsbereich 699).
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is published as part of the special issue on the Renin–Angiotensin System.
Rights and permissions
About this article
Cite this article
Wagner, C., Kurtz, A. Distribution and functional relevance of connexins in renin-producing cells. Pflugers Arch - Eur J Physiol 465, 71–77 (2013). https://doi.org/10.1007/s00424-012-1134-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-012-1134-7