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ScienceDirect Connexins, renin cell displacement and hypertension Armin Kurtz Vascular gap junctions formed by specific connexins proteins Cx37, 40, 43 and 45 are important for proper vascular function. This review outlines that defects of the connexin 40 protein leads to hypertension because of dysfunction of renin secreting cells of the kidney. Thus defects of Cx40 but not of other vascular connexins blunt the negative feedback control of renin secretion by the blood pressure, and moreover, lead to a shift of renin expression from the juxtaglomerular vessels walls into the periglomerular interstitium. Evidence exists to indicate that those findings which were primarily obtained with mice are also relevant for humans. Addresses Institute of Physiology, University of Regensburg, Germany Corresponding author: Kurtz, Armin ([email protected])
Current Opinion in Pharmacology 2015, 21:1–6 This review comes from a themed issue on Cardiovascular and renal
Connexins Gap junctions (GJs) are intercellular channels with a high permeability [2]. They serve to electrical impulse propagation and also to the exchange of signaling molecules with a molecular mass below 1 kD. GJs are formed by docking of two hemichannels (connexons) expressed by the two neighbored cells to be connected [2]. Beyond this classical view of GJs there is emerging evidence that also nonconnected hemichannels which allow communication between the intra-cellular and the extracellular space may play important physiological roles by the release of signaling molecules such as ATP [3]. Connexons are built up by six connexin proteins which assemble around a central pore. There exist 21 different connexin proteins in man and 20 in mice [4]. A connexon is normally formed by connexins of the same isoform (homomeric connexon), but also a mixture of two connexin isoforms within the same connexon may occur (heteromeric connexon). The type of the connexins determines the biophysical function of the connexon and if connected of the GJ.
Edited by Pernille BL Hansen and Boye L Jensen
http://dx.doi.org/10.1016/j.coph.2014.11.009 1471-4892/# 2014 Elsevier Ltd. All right reserved.
Introduction Hypertension is meanwhile a common disease with a high prevalence in industrial societies. The causes for hypertension are multifactorial. A substantial part of hypertensive diseases can be attributed to a dysfunction of the renin–angiotensin–aldosterone-system (RAAS), which normally plays an essential physiological role for the maintenance of normal sodium balance and of normal blood pressure [1]. The activity of the RAAS is triggered by the release of the protease renin from the kidneys. Inadequate secretion of renin is therefore a known reason of hypertension. During the last seven years a novel cellular mechanism has been identified that leads to hypersecretion of renin and to hypertension. This mechanism is related to disturbed intercellular communication of renin cells via gap junctions. It is the aim of the review to summarize the present state of knowledge how gap junctional coupling and control of renin secretion could be linked and how defective coupling could lead to hypertension. www.sciencedirect.com
Within the cardiovascular system GJs and connexons play an important role for intercellular communication in the heart, in the vascular endothelium, between vascular smooth muscle cells and between endothelial and smooth muscle cells. The cardiovascular GJs are mainly formed by Cx40, 43 and 45 in the heart [5–7] and by Cx37, 40, 43 and 45 in the vasculature [5,8–10]. Although there exist some regional heterogeneities within the vasculature, the endothelium normally expresses Cx37, Cx40 and also Cx43 [5,11,12], whereas smooth muscle cells mainly express Cx45 and Cx43 [8,13]. Myoendothelial junctions are probably formed by Cx37, Cx40 and Cx43 [14,15]. On the other hand interendothelial spreading of vasodilatory signals is dependent on Cx40 GJs [16,17].
Connexins and hypertension The regulation of GJ function either by modulation of connexon insertion into the membrane or by the physiological modulation of permeability of membrane inserted connexons in blood vessels is subject of increasing interest, but is still only poorly understood. There are findings that the expression of vascular connexins change in response to hypertension in a region dependent fashion suggesting secondary alterations of vascular functions induced by high blood pressure [18–20]. If connexins are important for proper vascular function [10] then primary alterations in the functions of vascular connexins would be expected to also alter vascular function [21]. This issue was addressed by generation of genetically engineered mice lacking these individual vascular connexin proteins. Whilst mice with conditional deletion of Current Opinion in Pharmacology 2015, 21:1–6
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Cx43 and of Cx45 are not viable because of defective cardiovascular development [4], do mice lacking either Cx37 or Cx40 survive and reach normal age. Cx37 deficient mice are normotensive but Cx40 deficient mice are hypertensive [22–24]. As Cx40 is essential for the spreading of vasodilatory signals along the endothelium [23,25] block of this spreading may cause the hypertension in these animals. However, it turned out that endothelium specific deletion of Cx40 exerts no influence on blood pressure [26]. The hypertension of Cx40 deficient mice is systolic and diastolic [25,26] (Figure 1) but is not salt sensitive, meaning that lowering or increasing salt intake does not change blood pressure [22,24]. Instead it turned out that inhibitors of the renin–angiotensin–aldosterone system (RAAS) such as ACE-inhibitors or inhibitors of angiotensin II-type 1 receptors (sartans) effectively rendered hypertensive Cx40 knockout mice normotensive [22,24]. In line, deletion of the angiotensin II-AT1a receptors in Cx40 deficient mice also makes them normotensive [27]. The conclusion from these findings, namely that the RAAS plays an important role for hypertension in Cx40 deficient mice, was corroborated by the findings that Cx40 deficient mice have high plasma renin concentrations [22,24] and also increased plasma aldosterone levels [27]. A causal role Figure 1
of renin and the RAAS for the hypertension in Cx40 deficient mice was further supported by the observation, that the hypertensive phenotype of Cx40 deficient mice could be mimicked by cell specific deletion of Cx40 in renin cells only [26], what is in line with the observation that intrarenal infusion of Cx40 mimetic peptides increases blood pressure [28]. In accordance with these findings it turned out that renin cells display strong expression of Cx40 [29–32] (Figure 2). The strong expression of Cx40 in renin cells and in the neighbored mesangial cells explained previous electron-microscopical findings about a high density of gap junctions between renin cells and mesangial cells [33,34]. In line, specific reintroduction of Cx40 in renin cells in mice with a global Cx40 deletion significantly ameliorates hypertension [35]. Whilst the demonstration of Cx40 renin cells was unequivocal, was a possible expression of other vascular connexins such as Cx37, 43 and 45 in renin cells more subject to discussion [30,31,36,37]. Regardless, specific deletion of any of these other connexins in renin cells produced no change of plasma renin activity or of blood pressure [36,38,39]. Conversely, the effect of Cx40 deletion on plasma renin and on blood pressure was mimicked by a mutation of the Cx40 protein, that strongly reduces the permeability of the Cx40 connexon [40,41]. This mutation leading to the exchange of serine at position 96 to alanine in the Cx40 protein was discovered in humans suffering from cardiac arrhythmia [40]. When inserted into mice the mutation caused increased plasma renin concentrations and hypertension [41]. In summary, there is convincing evidence to indicate
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Telemetry measurements of blood pressure in conscious mice lacking either connexin 40 selectively in renin cells (upper panel) or harboring a less of function mutation of Cx40 (lower panel). For details see text.Data are adapted from Refs. [24,25]. Current Opinion in Pharmacology 2015, 21:1–6
Mouse kidney section stained for connexin 40 (red color). There is intense Cx40 immunoreactivity in glomeruli, in particular in the intraand extraglomerular mesangium and in the renin cells (green color) located in the wall of the afferent arteriole. Blue color marks alphasmooth muscle actin delineating arteriolar vessel walls. www.sciencedirect.com
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that reduced function of Cx40 in renin cells of the kidney leads to hypersecretion of renin and thus contributes to the development of hypertension.
Cx40 related renin cell displacement and defective pressure control of renin secretion Normally, renin secretion and the resulting activity of the RAAS are effectively feedback regulated in the way that high blood pressure reduces the number of renin producing cells in the kidney and furthermore also inhibits renin secretion at the cellular level [42]. In states of hypotension the opposite occurs, the number of renin cells increases and renin secretion at the cellular level is disinhibited. The renin cells in the adult kidney normally form the media layer of the terminal parts of the afferent arterioles at the entrance into the glomeruli (socalled juxtaglomerular cells). When the number of renin cells increases in states of hypotension then additional smooth muscle cells in afferent arterioles metaplastically (without cell division) transform into renin producing cells and do so in a reversible fashion. In normal states of hypertension renin cells reversibly transform to smooth muscle cells [1]. Detailed analysis of renin secretion in Cx40 deficient mice revealed, that renin secretion did not respond to increased pressure with a suppression of secretion as normal but instead remained passive in this respect [24,43] (Figure 3). In addition, it turned out that in Figure 3
normal “renal baroreceptor” control
spite of hypertension an unexpected high number of renin cells persisted in the kidney, which however, were not localized in typical vascular position but instead in ectopic periglomerular position [41,43,44] (Figure 4). Therefore, the localization of the renin cells outside the vascular vessel wall might be a likely explanation why the cells do not sense the blood pressure appropriately and therefore release renin in a more uncontrolled fashion. Looking for an explanation for the ectopic localization of renin cells led to the assumption that Cx40 might be relevant for the homing of renin cells in the vascular wall of afferent arterioles. This assumption, however, turned out as false, because renin cells in the kidneys of Cx40 defective mice reappeared in the afferent vessel walls if the blood pressure was sufficiently lowered, whilst the ectopic renin cell remained independent of blood pressure [27]. The disappearance of vascular renin cells in Cx40 deficient mice therefore appears to be consequence of hypertension, whilst the appearance of ectopic periglomerular renin cells seems not to depend on hypertension. However, also in states in which vascular renin cells were found in Cx40 deficient mice, renin secretion from isolated perfused kidneys remained independent of perfusion pressure suggesting that Cx40 is important for the pressure control of renin secretion from individual vascular renin cells [27]. This conclusion is in accordance with the observation that nonselective chemical GJ inhibition also abrogates the pressure control from isolated perfused kidneys of normal mice [24]. In summary, it appears as if a defect of Cx40 function leads to an interruption of the pressure control of renin secretion Figure 4
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Dependency of renin secretion from isolated perfused mouse kidneys on the renal perfusion pressure. Red colored curve represents the normal kidneys, the blue colored curve represent states of defective Cx40 function. Data are adapted from Refs. [23,25,43]. Note that the typical inverse relationship between renin secretion and perfusion pressure is transformed into an almost linear positive relationship in states of Cx40 defects. www.sciencedirect.com
Schematic drawing demonstrating the localization of renin cells (green color) in normal kidneys (upper panel) and in kidneys with Cx40 defect (lower panel). EGM and IGM means extraglomerular mesangium and intraglomerular mesangium, respectively. Note the dislocation of renin cell from the walls of afferent arterioles to the periglomerular mesangium in states of defective Cx40 function. Current Opinion in Pharmacology 2015, 21:1–6
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leading to renin hypersecretion and to hypertension. Hypertension then causes downregulation of vascular renin expression what normally would be expected to relief renin secretion and to moderate hypertension. This however, does not occur, because in the absence of Cx40 ectopic periglomerular cells start to produce renin maintaining renin hypersecretion and hypertension. Since the findings described so far were obtained with animals that carried conditional defects of Cx40 function it is conceivable that the ectopic localization of renin cells may result from defective differentiation during kidney development. However, it turned out that deletion of Cx40 induced in normally developed kidneys also led to ectopic localization of renin cells [43]. In parallel, the pressure control of renin secretion became defective, plasma renin concentrations increased and the mice developed hypertension [43]. These findings suggest that defective Cx40 function in the periglomerular mesangial cells normally adjacent to renin cells activate the cells to express renin. To elucidate the underlying mechanisms by which lack of Cx40 induces ectopic renin expression remains a task for future research. The development of renin hypersecretion and of hypertension by inducible deletion of Cx40 in the adult kidney therefore opens a new field by suggesting that modifications of Cx40 occurring in renin cells of adult kidney may have impact for the activity of the RAAS and for blood pressure. There is increasing evidence for signaling pathways affecting membrane insertion or membrane retrieval of connexins or modulating connexon permeability [45]. There are also findings that metabolites such as lipids or inflammatory cytokines may downregulate Cx40 function [46–50]. In consequence of these findings one may speculate that metabolic disorders may change Cx40 function in renin cells and by that influence the RAAS and blood pressure.
Human aspects of Cx40 related hypertension Findings obtained in laboratory animals more generally raise the question about their relevance in humans. In general, it can be stated that the principles of the regulation of renin and of the RAAS are similar between man and laboratory rodents. In line, also renin cells of human kidney have been found to strongly express connexin 40 [51]. Moreover, polymorphisms in the Cx40 promotor have been associated with hypertension in humans [52]. There is also an increasing number of Cx40 mutations described in humans [53,54], which however, are primarily characterized with regard to their cardiac phenotype, which guided the identification of the mutation. These mutations have so far been only rarely considered in context with the blood pressure phenotype, because blood pressure aberrations can be multifactorial. One human loss of function mutation of Cx40 identified in humans [40] has been inserted into mice and was found Current Opinion in Pharmacology 2015, 21:1–6
to produce hypertension [41]. The induction of hypertension in mice required homozygous mutations [41], whilst the cardiac phenotype in the patients was already seen in heterozygous mutations [40]. However, it should be mentioned that the Cx40 mutation leads to defective intracellular trafficking in the myocardium [55], whilst in renin cells mutated Cx40 is expressed in the membrane [41]. Therefore, the gene dosage effect of the Cx40 mutation may depend on the tissue making a direct comparison of the effects on heart function and on the RAAS more difficult. Data summarized so far strongly suggest that altered function of Cx40 in renin cells can cause hypertension. If overactivation of the RAAS, however, exclusively explains the hypertension seen in mice with defective Cx40 function is not entirely clear. As already mentioned, there is compelling evidence to indicate that RAAS inhibition lowers blood pressure in Cx40 defective mice to normal values [22,23,24,27,56]. At the same time, however, produce these maneuvers also a lowering of blood pressure in mice with intact Cx40 function [22,23,24,27,56]. As a consequence a certain blood pressure difference remains between intact mice and Cx40 defective mice during RAAS blockade. The amplitude of this remaining difference varies between the different studies that have addressed this issue so far. In the majority of studies, however, was the blood pressure lowering effect of RAAS inhibition greater in Cx40 deficient than in normal mice, supporting the assumption that overactivity of the RAAS plays an important role for the development of hypertension in states of defective Cx40 function. If a RAAS independent component of hypertension really exists and what its cause could be remains to be clarified.
Conflict of interest statement None declared.
Acknowledgement The author gratefully acknowledges support from the Deutsche Forschungsgemeinschaft (DFG, SFB 699).
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
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24. Wagner C, de Wit C, Kurtz L, Grunberger C, Kurtz A, Schweda F: Connexin40 is essential for the pressure control of renin synthesis and secretion. Circ Res 2007, 100:556-563. 25. Jobs A, Schmidt K, Schmidt VJ, Lubkemeier I, van Veen TA, Kurtz A, Willecke K, de Wit C: Defective Cx40 maintains Cx37 expression but intact Cx40 is crucial for conducted dilations irrespective of hypertension. Hypertension 2012, 60:1422-1429. Together with [21,23,34], this manuscript highlights the relevance of Cx40 for renin secretion and blood pressure. 26. Wagner C, Jobs A, Schweda F, Kurtz L, Kurt B, Lopez ML, Gomez RA, van Veen TA, de Wit C, Kurtz A: Selective deletion of connexin 40 in renin-producing cells impairs renal baroreceptor function and is associated with arterial hypertension. Kidney Int 2010, 78:762-768. This manuscript provides evidence that the ectopic localization of Cx40 deficient renin cell is the reason for rather than the consequence of hypertension. 27. Machura K, Neubauer B, Muller H, Tauber P, Kurtz A, Kurtz L: Connexin 40 is dispensable for vascular renin cell recruitment but is indispensable for vascular baroreceptor control of renin secretion. Pflugers Arch 2014. PubMed ID: 25241776. 28. De Vriese AS, Van de Voorde J, Lameire NH: Effects of connexinmimetic peptides on nitric oxide synthase- and cyclooxygenase-independent renal vasodilation. Kidney Int 2002, 61:177-185. 29. Takenaka T, Inoue T, Kanno Y, Okada H, Meaney KR, Hill CE, Suzuki H: Expression and role of connexins in the rat renal vasculature. Kidney Int 2008, 73:415-422. 30. KurtzL,Janssen-BienholdU,KurtzA,WagnerC:Connexinexpression in renin-producing cells. J Am Soc Nephrol 2009, 20:506-512. 31. Zhang J, Hill CE: Differential connexin expression in preglomerular and postglomerular vasculature: accentuation during diabetes. Kidney Int 2005, 68:1171-1185. 32. Hwan Seul K, Beyer EC: Heterogeneous localization of connexin40 in the renal vasculature. Microvasc Res 2000, 59:140-148. 33. Taugner R, Schiller A, Kaissling B, Kriz W: Gap junctional coupling between the JGA and the glomerular tuft. Cell Tissue Res 1978, 186:279-285. 34. Spanidis A, Wunsch H, Kaissling B, Kriz W: Three-dimensional shape of a Goormaghtigh cell and its contact with a granular cell in the rabbit kidney. Anat Embryol (Berl) 1982, 165:239-252. Together with [21,23,25], this manuscript highlights the relevance of Cx40 for renin secretion and blood pressure.
17. de Wit C, Hoepfl B, Wolfle SE: Endothelial mediators and communication through vascular gap junctions. Biol Chem 2006, 387:3-9.
35. Le Gal L, Alonso F, Wagner C, Germain S, Nardelli Haefliger D, Meda P, Haefliger JA: Restoration of connexin 40 (Cx40) in renin-producing cells reduces the hypertension of Cx40 null mice. Hypertension 2014, 63:1198-1204.
18. Haefliger JA, Demotz S, Braissant O, Suter E, Waeber B, Nicod P, Meda P: Connexins 40 and 43 are differentially regulated within the kidneys of rats with renovascular hypertension. Kidney Int 2001, 60:190-201.
36. Kurt B, Kurtz L, Sequeira-Lopez ML, Gomez RA, Willecke K, Wagner C, Kurtz A: Reciprocal expression of connexin 40 and 45 during phenotypical changes in renin-secreting cells. Am J Physiol Renal Physiol 2011, 300:F743-F748.
19. Braunstein TH, Sorensen CM, Holstein-Rathlou NH: Connexin abundance in resistance vessels from the renal microcirculation in normo- and hypertensive rats. APMIS 2009, 117:268-276.
37. Hanner F, von Maltzahn J, Maxeiner S, Toma I, Sipos A, Kruger O, Willecke K, Peti-Peterdi J: 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 2008, 295:R371-R380.
20. Figueroa XF, Isakson BE, Duling BR: Vascular gap junctions in hypertension. Hypertension 2006, 48:804-811. 21. Pfenniger A, Chanson M, Kwak BR: Connexins in atherosclerosis. Biochim Biophys Acta 2013, 1828:157-166. Together with [23,25,34], this manuscript highlights the relevance of Cx40 for renin secretion and blood pressure. 22. Krattinger N, Capponi A, Mazzolai L, Aubert JF, Caille D, Nicod P, Waeber G, Meda P, Haefliger JA: Connexin40 regulates renin production and blood pressure. Kidney Int 2007, 72:814-822. 23. de Wit C, Roos F, Bolz SS, Pohl U: Lack of vascular connexin 40 is associated with hypertension and irregular arteriolar vasomotion. Physiol Genomics 2003, 13:169-177. Together with [21,25,34], this manuscript highlights the relevance of Cx40 for renin secretion and blood pressure. www.sciencedirect.com
38. Wagner C, Kurtz L, Schweda F, Simon AM, Kurtz A: Connexin 37 is dispensable for the control of the renin system and for positioning of renin-producing cells in the kidney. Pflugers Arch 2009, 459:151-158. 39. Gerl M, Kurt B, Kurtz A, Wagner C: Connexin 43 is not essential for the control of renin synthesis and secretion. Pflugers Arch 2014, 466:1003-1009. 40. Gollob MH, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q, Liu X, Veinot JP, Tang AS, Stewart AF et al.: Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med 2006, 354:2677-2688. This manuscript describes that a single mutation of Cx40 discovered in humans produces hypersecretion of renin and hypertension when inserted into mice. Current Opinion in Pharmacology 2015, 21:1–6
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41. Lubkemeier I, Machura K, Kurtz L, Neubauer B, Dobrowolski R, Schweda F, Wagner C, Willecke K, Kurtz A: The connexin 40 A96S mutation causes renin-dependent hypertension. J Am Soc Nephrol 2011, 22:1031-1040. 42. Schweda F, Friis U, Wagner C, Skott O, Kurtz A: Renin release. Physiology (Bethesda) 2007, 22:310-319. 43. Gerl M, Vockl J, Kurt B, van Veen TA, Kurtz A, Wagner C: Inducible deletion of connexin 40 in adult mice causes hypertension and disrupts pressure control of renin secretion. Kidney Int 2014. This manuscript describes that the phenotypic changes occurring in Cx40 deficient mice can be induced in the adult mouse. 44. Kurtz L, Schweda F, de Wit C, Kriz W, Witzgall R, Warth R, Sauter A, Kurtz A, Wagner C: Lack of connexin 40 causes displacement of renin-producing cells from afferent arterioles to the extraglomerular mesangium. J Am Soc Nephrol 2007, 18:1103-1111. This manuscript describes the ectopic localization of renin cells in Cx40 deficient kidneys. 45. Su V, Lau AF: Connexins: mechanisms regulating protein levels and intercellular communication. FEBS Lett 2014, 588:12121220. 46. Isakson BE, Kronke G, Kadl A, Leitinger N, Duling BR: Oxidized phospholipids alter vascular connexin expression, phosphorylation, and heterocellular communication. Arterioscler Thromb Vasc Biol 2006, 26:2216-2221.
49. Yeh HI, Lu CS, Wu YJ, Chen CC, Hong RC, Ko YS, Shiao MS, Severs NJ, Tsai CH: Reduced expression of endothelial connexin37 and connexin40 in hyperlipidemic mice: recovery of connexin37 after 7-day simvastatin treatment. Arterioscler Thromb Vasc Biol 2003, 23:1391-1397. 50. Hou CJ, Tsai CH, Su CH, Wu YJ, Chen SJ, Chiu JJ, Shiao MS, Yeh HI: Diabetes reduces aortic endothelial gap junctions in ApoE-deficient mice: simvastatin exacerbates the reduction. J Histochem Cytochem 2008, 56:745-752. 51. Kurtz L, Madsen K, Kurt B, Jensen BL, Walter S, Banas B, Wagner C, Kurtz A: High-level connexin expression in the human juxtaglomerular apparatus. Nephron Physiol 2010, 116:1-8. 52. Firouzi M, Kok B, Spiering W, Busjahn A, Bezzina CR, Ruijter JM, Koeleman BP, Schipper M, Groenewegen WA, Jongsma HJ et al.: Polymorphisms in human connexin40 gene promoter are associated with increased risk of hypertension in men. J Hypertens 2006, 24:325-330. 53. Molica F, Meens MJ, Morel S, Kwak BR: Mutations in cardiovascular connexin genes. Biol Cell 2014, 106:269-293. 54. Bai D: Atrial fibrillation-linked GJA5/connexin40 mutants impaired gap junctions via different mechanisms. FEBS Lett 2014, 588:1238-1243.
47. Zhang JH, Kawashima S, Yokoyama M, Huang P, Hill CE: Increased eNOS accounts for changes in connexin expression in renal arterioles during diabetes. Anat Rec A Discov Mol Cell Evol Biol 2006, 288:1000-1008.
55. Lubkemeier I, Andrie R, Lickfett L, Bosen F, Stockigt F, Dobrowolski R, Draffehn AM, Fregeac J, Schultze JL, Bukauskas FF et al.: The Connexin40A96S mutation from a patient with atrial fibrillation causes decreased atrial conduction velocities and sustained episodes of induced atrial fibrillation in mice. J Mol Cell Cardiol 2013, 65:19-32.
48. Rignault S, Haefliger JA, Gasser D, Markert M, Nicod P, Liaudet L, Waeber B, Feihl F: Sepsis up-regulates the expression of connexin 40 in rat aortic endothelium. Crit Care Med 2005, 33:1302-1310.
56. Krattinger N, Alonso F, Capponi A, Mazzolai L, Nicod P, Meda P, Haefliger JA: Increased expression of renal cyclooxygenase-2 and neuronal nitric oxide synthase in hypertensive Cx40deficient mice. J Vasc Res 2009, 46:188-198.
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ScienceDirect Connexins, renin cell displacement and hypertension Armin Kurtz Vascular gap junctions formed by specific connexins proteins Cx37, 40, 43 and 45 are important for proper vascular function. This review outlines that defects of the connexin 40 protein leads to hypertension because of dysfunction of renin secreting cells of the kidney. Thus defects of Cx40 but not of other vascular connexins blunt the negative feedback control of renin secretion by the blood pressure, and moreover, lead to a shift of renin expression from the juxtaglomerular vessels walls into the periglomerular interstitium. Evidence exists to indicate that those findings which were primarily obtained with mice are also relevant for humans. Addresses Institute of Physiology, University of Regensburg, Germany Corresponding author: Kurtz, Armin ([email protected])
Current Opinion in Pharmacology 2015, 21:1–6 This review comes from a themed issue on Cardiovascular and renal
Connexins Gap junctions (GJs) are intercellular channels with a high permeability [2]. They serve to electrical impulse propagation and also to the exchange of signaling molecules with a molecular mass below 1 kD. GJs are formed by docking of two hemichannels (connexons) expressed by the two neighbored cells to be connected [2]. Beyond this classical view of GJs there is emerging evidence that also nonconnected hemichannels which allow communication between the intra-cellular and the extracellular space may play important physiological roles by the release of signaling molecules such as ATP [3]. Connexons are built up by six connexin proteins which assemble around a central pore. There exist 21 different connexin proteins in man and 20 in mice [4]. A connexon is normally formed by connexins of the same isoform (homomeric connexon), but also a mixture of two connexin isoforms within the same connexon may occur (heteromeric connexon). The type of the connexins determines the biophysical function of the connexon and if connected of the GJ.
Edited by Pernille BL Hansen and Boye L Jensen
http://dx.doi.org/10.1016/j.coph.2014.11.009 1471-4892/# 2014 Elsevier Ltd. All right reserved.
Introduction Hypertension is meanwhile a common disease with a high prevalence in industrial societies. The causes for hypertension are multifactorial. A substantial part of hypertensive diseases can be attributed to a dysfunction of the renin–angiotensin–aldosterone-system (RAAS), which normally plays an essential physiological role for the maintenance of normal sodium balance and of normal blood pressure [1]. The activity of the RAAS is triggered by the release of the protease renin from the kidneys. Inadequate secretion of renin is therefore a known reason of hypertension. During the last seven years a novel cellular mechanism has been identified that leads to hypersecretion of renin and to hypertension. This mechanism is related to disturbed intercellular communication of renin cells via gap junctions. It is the aim of the review to summarize the present state of knowledge how gap junctional coupling and control of renin secretion could be linked and how defective coupling could lead to hypertension. www.sciencedirect.com
Within the cardiovascular system GJs and connexons play an important role for intercellular communication in the heart, in the vascular endothelium, between vascular smooth muscle cells and between endothelial and smooth muscle cells. The cardiovascular GJs are mainly formed by Cx40, 43 and 45 in the heart [5–7] and by Cx37, 40, 43 and 45 in the vasculature [5,8–10]. Although there exist some regional heterogeneities within the vasculature, the endothelium normally expresses Cx37, Cx40 and also Cx43 [5,11,12], whereas smooth muscle cells mainly express Cx45 and Cx43 [8,13]. Myoendothelial junctions are probably formed by Cx37, Cx40 and Cx43 [14,15]. On the other hand interendothelial spreading of vasodilatory signals is dependent on Cx40 GJs [16,17].
Connexins and hypertension The regulation of GJ function either by modulation of connexon insertion into the membrane or by the physiological modulation of permeability of membrane inserted connexons in blood vessels is subject of increasing interest, but is still only poorly understood. There are findings that the expression of vascular connexins change in response to hypertension in a region dependent fashion suggesting secondary alterations of vascular functions induced by high blood pressure [18–20]. If connexins are important for proper vascular function [10] then primary alterations in the functions of vascular connexins would be expected to also alter vascular function [21]. This issue was addressed by generation of genetically engineered mice lacking these individual vascular connexin proteins. Whilst mice with conditional deletion of Current Opinion in Pharmacology 2015, 21:1–6
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Cx43 and of Cx45 are not viable because of defective cardiovascular development [4], do mice lacking either Cx37 or Cx40 survive and reach normal age. Cx37 deficient mice are normotensive but Cx40 deficient mice are hypertensive [22–24]. As Cx40 is essential for the spreading of vasodilatory signals along the endothelium [23,25] block of this spreading may cause the hypertension in these animals. However, it turned out that endothelium specific deletion of Cx40 exerts no influence on blood pressure [26]. The hypertension of Cx40 deficient mice is systolic and diastolic [25,26] (Figure 1) but is not salt sensitive, meaning that lowering or increasing salt intake does not change blood pressure [22,24]. Instead it turned out that inhibitors of the renin–angiotensin–aldosterone system (RAAS) such as ACE-inhibitors or inhibitors of angiotensin II-type 1 receptors (sartans) effectively rendered hypertensive Cx40 knockout mice normotensive [22,24]. In line, deletion of the angiotensin II-AT1a receptors in Cx40 deficient mice also makes them normotensive [27]. The conclusion from these findings, namely that the RAAS plays an important role for hypertension in Cx40 deficient mice, was corroborated by the findings that Cx40 deficient mice have high plasma renin concentrations [22,24] and also increased plasma aldosterone levels [27]. A causal role Figure 1
of renin and the RAAS for the hypertension in Cx40 deficient mice was further supported by the observation, that the hypertensive phenotype of Cx40 deficient mice could be mimicked by cell specific deletion of Cx40 in renin cells only [26], what is in line with the observation that intrarenal infusion of Cx40 mimetic peptides increases blood pressure [28]. In accordance with these findings it turned out that renin cells display strong expression of Cx40 [29–32] (Figure 2). The strong expression of Cx40 in renin cells and in the neighbored mesangial cells explained previous electron-microscopical findings about a high density of gap junctions between renin cells and mesangial cells [33,34]. In line, specific reintroduction of Cx40 in renin cells in mice with a global Cx40 deletion significantly ameliorates hypertension [35]. Whilst the demonstration of Cx40 renin cells was unequivocal, was a possible expression of other vascular connexins such as Cx37, 43 and 45 in renin cells more subject to discussion [30,31,36,37]. Regardless, specific deletion of any of these other connexins in renin cells produced no change of plasma renin activity or of blood pressure [36,38,39]. Conversely, the effect of Cx40 deletion on plasma renin and on blood pressure was mimicked by a mutation of the Cx40 protein, that strongly reduces the permeability of the Cx40 connexon [40,41]. This mutation leading to the exchange of serine at position 96 to alanine in the Cx40 protein was discovered in humans suffering from cardiac arrhythmia [40]. When inserted into mice the mutation caused increased plasma renin concentrations and hypertension [41]. In summary, there is convincing evidence to indicate
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Telemetry measurements of blood pressure in conscious mice lacking either connexin 40 selectively in renin cells (upper panel) or harboring a less of function mutation of Cx40 (lower panel). For details see text.Data are adapted from Refs. [24,25]. Current Opinion in Pharmacology 2015, 21:1–6
Mouse kidney section stained for connexin 40 (red color). There is intense Cx40 immunoreactivity in glomeruli, in particular in the intraand extraglomerular mesangium and in the renin cells (green color) located in the wall of the afferent arteriole. Blue color marks alphasmooth muscle actin delineating arteriolar vessel walls. www.sciencedirect.com
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that reduced function of Cx40 in renin cells of the kidney leads to hypersecretion of renin and thus contributes to the development of hypertension.
Cx40 related renin cell displacement and defective pressure control of renin secretion Normally, renin secretion and the resulting activity of the RAAS are effectively feedback regulated in the way that high blood pressure reduces the number of renin producing cells in the kidney and furthermore also inhibits renin secretion at the cellular level [42]. In states of hypotension the opposite occurs, the number of renin cells increases and renin secretion at the cellular level is disinhibited. The renin cells in the adult kidney normally form the media layer of the terminal parts of the afferent arterioles at the entrance into the glomeruli (socalled juxtaglomerular cells). When the number of renin cells increases in states of hypotension then additional smooth muscle cells in afferent arterioles metaplastically (without cell division) transform into renin producing cells and do so in a reversible fashion. In normal states of hypertension renin cells reversibly transform to smooth muscle cells [1]. Detailed analysis of renin secretion in Cx40 deficient mice revealed, that renin secretion did not respond to increased pressure with a suppression of secretion as normal but instead remained passive in this respect [24,43] (Figure 3). In addition, it turned out that in Figure 3
normal “renal baroreceptor” control
spite of hypertension an unexpected high number of renin cells persisted in the kidney, which however, were not localized in typical vascular position but instead in ectopic periglomerular position [41,43,44] (Figure 4). Therefore, the localization of the renin cells outside the vascular vessel wall might be a likely explanation why the cells do not sense the blood pressure appropriately and therefore release renin in a more uncontrolled fashion. Looking for an explanation for the ectopic localization of renin cells led to the assumption that Cx40 might be relevant for the homing of renin cells in the vascular wall of afferent arterioles. This assumption, however, turned out as false, because renin cells in the kidneys of Cx40 defective mice reappeared in the afferent vessel walls if the blood pressure was sufficiently lowered, whilst the ectopic renin cell remained independent of blood pressure [27]. The disappearance of vascular renin cells in Cx40 deficient mice therefore appears to be consequence of hypertension, whilst the appearance of ectopic periglomerular renin cells seems not to depend on hypertension. However, also in states in which vascular renin cells were found in Cx40 deficient mice, renin secretion from isolated perfused kidneys remained independent of perfusion pressure suggesting that Cx40 is important for the pressure control of renin secretion from individual vascular renin cells [27]. This conclusion is in accordance with the observation that nonselective chemical GJ inhibition also abrogates the pressure control from isolated perfused kidneys of normal mice [24]. In summary, it appears as if a defect of Cx40 function leads to an interruption of the pressure control of renin secretion Figure 4
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Dependency of renin secretion from isolated perfused mouse kidneys on the renal perfusion pressure. Red colored curve represents the normal kidneys, the blue colored curve represent states of defective Cx40 function. Data are adapted from Refs. [23,25,43]. Note that the typical inverse relationship between renin secretion and perfusion pressure is transformed into an almost linear positive relationship in states of Cx40 defects. www.sciencedirect.com
Schematic drawing demonstrating the localization of renin cells (green color) in normal kidneys (upper panel) and in kidneys with Cx40 defect (lower panel). EGM and IGM means extraglomerular mesangium and intraglomerular mesangium, respectively. Note the dislocation of renin cell from the walls of afferent arterioles to the periglomerular mesangium in states of defective Cx40 function. Current Opinion in Pharmacology 2015, 21:1–6
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leading to renin hypersecretion and to hypertension. Hypertension then causes downregulation of vascular renin expression what normally would be expected to relief renin secretion and to moderate hypertension. This however, does not occur, because in the absence of Cx40 ectopic periglomerular cells start to produce renin maintaining renin hypersecretion and hypertension. Since the findings described so far were obtained with animals that carried conditional defects of Cx40 function it is conceivable that the ectopic localization of renin cells may result from defective differentiation during kidney development. However, it turned out that deletion of Cx40 induced in normally developed kidneys also led to ectopic localization of renin cells [43]. In parallel, the pressure control of renin secretion became defective, plasma renin concentrations increased and the mice developed hypertension [43]. These findings suggest that defective Cx40 function in the periglomerular mesangial cells normally adjacent to renin cells activate the cells to express renin. To elucidate the underlying mechanisms by which lack of Cx40 induces ectopic renin expression remains a task for future research. The development of renin hypersecretion and of hypertension by inducible deletion of Cx40 in the adult kidney therefore opens a new field by suggesting that modifications of Cx40 occurring in renin cells of adult kidney may have impact for the activity of the RAAS and for blood pressure. There is increasing evidence for signaling pathways affecting membrane insertion or membrane retrieval of connexins or modulating connexon permeability [45]. There are also findings that metabolites such as lipids or inflammatory cytokines may downregulate Cx40 function [46–50]. In consequence of these findings one may speculate that metabolic disorders may change Cx40 function in renin cells and by that influence the RAAS and blood pressure.
Human aspects of Cx40 related hypertension Findings obtained in laboratory animals more generally raise the question about their relevance in humans. In general, it can be stated that the principles of the regulation of renin and of the RAAS are similar between man and laboratory rodents. In line, also renin cells of human kidney have been found to strongly express connexin 40 [51]. Moreover, polymorphisms in the Cx40 promotor have been associated with hypertension in humans [52]. There is also an increasing number of Cx40 mutations described in humans [53,54], which however, are primarily characterized with regard to their cardiac phenotype, which guided the identification of the mutation. These mutations have so far been only rarely considered in context with the blood pressure phenotype, because blood pressure aberrations can be multifactorial. One human loss of function mutation of Cx40 identified in humans [40] has been inserted into mice and was found Current Opinion in Pharmacology 2015, 21:1–6
to produce hypertension [41]. The induction of hypertension in mice required homozygous mutations [41], whilst the cardiac phenotype in the patients was already seen in heterozygous mutations [40]. However, it should be mentioned that the Cx40 mutation leads to defective intracellular trafficking in the myocardium [55], whilst in renin cells mutated Cx40 is expressed in the membrane [41]. Therefore, the gene dosage effect of the Cx40 mutation may depend on the tissue making a direct comparison of the effects on heart function and on the RAAS more difficult. Data summarized so far strongly suggest that altered function of Cx40 in renin cells can cause hypertension. If overactivation of the RAAS, however, exclusively explains the hypertension seen in mice with defective Cx40 function is not entirely clear. As already mentioned, there is compelling evidence to indicate that RAAS inhibition lowers blood pressure in Cx40 defective mice to normal values [22,23,24,27,56]. At the same time, however, produce these maneuvers also a lowering of blood pressure in mice with intact Cx40 function [22,23,24,27,56]. As a consequence a certain blood pressure difference remains between intact mice and Cx40 defective mice during RAAS blockade. The amplitude of this remaining difference varies between the different studies that have addressed this issue so far. In the majority of studies, however, was the blood pressure lowering effect of RAAS inhibition greater in Cx40 deficient than in normal mice, supporting the assumption that overactivity of the RAAS plays an important role for the development of hypertension in states of defective Cx40 function. If a RAAS independent component of hypertension really exists and what its cause could be remains to be clarified.
Conflict of interest statement None declared.
Acknowledgement The author gratefully acknowledges support from the Deutsche Forschungsgemeinschaft (DFG, SFB 699).
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
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