Abstract
The juxtaglomerular areas of mammalian kidneys express the gap junction proteins connexin 37, 40, 43, and 45. Among these, Cx40 plays a major role for the function of juxtaglomerular renin-expressing cells, while Cx37 and Cx45 appear to be less relevant in this context. Since the role of the remaining Cx43 for the function of renin expression is not well understood, this study aimed to systematically characterize the direct role of Cx43 for renin expression and secretion. For this aim, we generated mice with endothelium and with renin cell-specific deletions of Cx43, and we characterized the regulation of renin expression and renin secretion in the kidneys of these mice on normal salt diet and during chronic challenge of the renin system by pretreatment of mice with a low-salt diet in combination with an angiotensin I-converting enzyme inhibitor. We found that renal renin mRNA abundance, plasma renin concentration, and systolic blood pressure did not differ between wild-type, Cx43fl/fl Ren1d+/Cre mice as well as Cx43fl/fl Tie-2+/Cre mice under basal conditions nor under chronic stimulation by salt depletion. The localization of renin-expressing cells was also regular in kidneys of all genotypes, and moreover, regulation of renin secretion by beta-adrenergic stimulation and renal perfusion pressure measured in isolated perfused kidneys of Cx43fl/fl Ren1d+/Cre and Cx43fl/fl Tie-2+/Cre mice was not different from control. We infer from these results that Cx43 plays if at all only a minor role for the functional control of renin-producing cells in the kidney.
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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 115:479–87
Cottrell GT, Burt JM (2001) Heterotypic gap junction channel formation between heteromeric and homomeric Cx40 and Cx43 connexons. Am J Physiol Cell Physiol 281:C1559–67
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. doi:10.1046/j.1523-1755.2001.00786.×
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. doi:10.1172/JCI23327
Haefliger JA, Nicod P, Meda P (2004) Contribution of connexins to the function of the vascular wall. Cardiovasc Res 62:345–356. doi:10.1016/j.cardiores.2003.11.015
Hanner F, Sorensen CM, Holstein-Rathlou NH, Peti-Peterdi J (2010) Connexins and the kidney. Am J Physiol Regul Integr Comp Physiol 298:R1143–R1155. doi:10.1152/ajpregu.00808.2009
He DS, Jiang JX, Taffet SM, Burt JM (1999) Formation of heteromeric gap junction channels by connexins 40 and 43 in vascular smooth muscle cells. Proc Natl Acad Sci USA 96:6495–500
Hwan Seul K, Beyer EC (2000) Heterogeneous localization of connexin40 in the renal vasculature. Microvasc Res 59:140–148. doi:10.1006/mvre.1999.2216
Isakson BE, Duling BR (2005) Heterocellular contact at the myoendothelial junction influences gap junction organization. Circ Res 97:44–51. doi:10.1161/01.RES.0000173461.36221.2e
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. doi:10.1038/sj.ki.5002423
Kurtz L, Janssen-Bienhold U, Kurtz A, Wagner C (2009) Connexin expression in renin-producing cells. J Am Soc Nephrol 20:506–512. doi:10.1681/ASN.2008030252
Kurtz L, Madsen K, Kurt B, Jensen BL, Walter S, Banas B, Wagner C, Kurtz A (2010) High-level connexin expression in the human juxtaglomerular apparatus. Nephron Physiol 116:p1–p8. doi:10.1159/000315658
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. doi:10.1681/ASN.2006090953
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. doi:10.1073/pnas.171305298
Lopez D, Rodriguez-Sinovas A, Agullo E, Garcia A, Sanchez JA, Garcia-Dorado D (2009) Replacement of connexin 43 by connexin 32 in a knock-in mice model attenuates aortic endothelium-derived hyperpolarizing factor-mediated relaxation. Exp Physiol 94:1088–1097. doi:10.1113/expphysiol.2009.048413
Sauter A, Machura K, Neubauer B, Kurtz A, Wagner C (2008) Development of renin expression in the mouse kidney. Kidney Int 73:43–51. doi:10.1038/sj.ki.5002571
Sorensen CM, Holstein-Rathlou NH (2012) Cell-cell communication in the kidney microcirculation. Microcirculation 19:451–460. doi:10.1111/j.1549-8719.2011.00149.×
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. doi:10.1038/sj.ki.5002673
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
Valiunas V, Gemel J, Brink PR, Beyer EC (2001) Gap junction channels formed by coexpressed connexin40 and connexin43. Am J Physiol Heart Circ Physiol 281:H1675–89
Wagner C (2008) Function of connexins in the renal circulation. Kidney Int 73:547–555. doi:10.1038/sj.ki.5002720
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. doi:10.1161/01.RES.0000258856.19922.45
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. doi:10.1038/ki.2010.257
Wagner C, Kurtz A (2013) Distribution and functional relevance of connexins in renin-producing cells. Pflugers Arch 465:71–77. doi:10.1007/s00424-012-1134-7
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. doi:10.1007/s00424-009-0707-6
Acknowledgments
We are very grateful to Anna M’Bangui, Marcela DeLoza, and Gerda Treuner for helpful technical assistance. The authors’ work was financially supported by Deutsche Forschungsgemeinschaft Grant (WA-2137/2-2).
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Gerl, M., Kurt, B., Kurtz, A. et al. Connexin 43 is not essential for the control of renin synthesis and secretion. Pflugers Arch - Eur J Physiol 466, 1003–1009 (2014). https://doi.org/10.1007/s00424-013-1349-2
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DOI: https://doi.org/10.1007/s00424-013-1349-2