- Email: [email protected]
Hypertension in connexin40-null mice: a renin disorder
co m m e nt a r y
2.
3.
4.
5.
6.
7.
8.
9. 10.
11.
12.
13. 14.
15.
16.
17.
18.
Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA. Division of Kidney, Urologic, and Hematologic Diseases Annual, Data Report 2005, pp128–129. Go AS, Chertow GM, Fan D et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 1296–1305. Lowrie EG, Lew NL. Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 1990; 15: 458–482. Iseki K, Yamazato M, Tozawa M, Takishita S. Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients. Kidney Int 2002; 61: 1887–1893. Stompor T, Pasowicz M, Sullowicz W et al. An association between coronary artery calcification score, lipid profile, and selected markers of chronic inflammation in ESRD patients treated with peritoneal dialysis. Am J Kidney Dis 2003; 41: 203–211. Shoji T, Nishizawa Y, Kawagishi T et al. Intermediatedensity lipoprotein as an independent risk factor for aortic atherosclerosis in hemodialysis patients. J Am Soc Nephrol 1998; 9: 1277–1284. Koch M, Kutkuhn B, Grabensee B, Ritz E. Apolipoprotein A, fibrinogen, age, and history of stroke are predictors of death in dialysed diabetic patients: a prospective study in 412 subjects. Nephrol Dial Transplant 1997; 12: 2603–2611. Okubo K, Ikewaki K, Sakai S et al. Abnormal HDL apolipoprotein A-I and A-II kinetics in hemodialysis patients: a stable isotope study. J Am Soc Nephrol 2004; 15: 1008–1015. Kaysen GA. Disorders in high-density metabolism with insulin resistance and chronic kidney disease. J Ren Nutr 2007; 17: 4–8. Ikewaki K, Schaefer JR, Frischmann ME et al. Delayed in vivo catabolism of intermediatedensity lipoprotein and low-density lipoprotein in hemodialysis patients as potential cause of premature atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25: 2615–2622. Walzem RL, Watkins S, Frankel EN et al. Older plasma lipoproteins are more susceptible to oxidation: a linking mechanism for the lipid and oxidation theories of atherosclerotic cardiovascular disease. Proc Natl Acad Sci USA 1995; 92: 7460–7464. Chan MK, Persaud J, Varghese Z, Moorhead JF. Pathogenic roles of post-heparin lipases in lipid abnormalities in hemodialysis patients. Kidney Int 1984; 25: 812–818. Kim C, Vaziri ND. Down-regulation of hepatic LDL receptor-related protein (LRP) in chronic renal failure. Kidney Int 2005; 67: 1028–1032. Lee DM, Knight-Gibson C, Samuelsson O et al. Lipoprotein particle abnormalities and the impaired lipolysis in renal insufficiency. Kidney Int 2002; 61: 209–218. Dautin G, Soltani Z, Ducloux D et al. Hemodialysis reduces plasma apolipoprotein C-I concentration making VLDL a better substrate for lipoprotein lipase. Kidney Int 2007; 72: 871–878. Swaney JB, Weisgraber KH. Effect of apolipoprotein C-I peptides on the apolipoprotein E content and receptor-binding properties of beta-migrating very low density lipoproteins. J Lipid Res 1994; 35: 134–142. van der Hoogt CC, Berbee JF, Espirito et al. Apolipoprotein CI causes hypertriglyceridemia independent of the very-low-density lipoprotein receptor and apolipoprotein CIII in mice. Biochim Biophys Acta 2006; 1761: 213–220. Berbee JF, van der Hoogt CC, Sundararaman D et
Kidney International (2007) 72
al. Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL. J Lipid Res 2005; 46: 297–306. 19. Mekki K, Bouchenak M, Remaoun M, Belleville JL. Effect of long-term hemodialysis on plasma lecithin: cholesterol acyltransferase activity and the amounts and compositions of HDL2 and HDL3 in hemodialysis-treated patients with chronic renal failure. A 9-year longitudinal study. Med Sci Monit 2004; 10: CR439–CR446. 20. Dumont L, Gautier T, de Barros JP et al. Molecular mechanism of the blockade of plasma cholesteryl ester transfer protein by its physiological inhibitor apolipoprotein CI. J Biol Chem 2005; 280: 38108–38116.
21. Bondarenko PV, Cockrill SL, Watkins LK et al. Mass spectral study of polymorphism of the apolipoproteins of very low density lipoprotein. J Lipid Res 1999; 40: 543–555. 22. Swaney JB, Weisgraber KH. Effect of apolipoprotein C-I peptides on the apolipoprotein E content and receptor-binding properties of beta-migrating very low density lipoproteins. J Lipid Res 1994; 35: 134–142. 23. Wanner C, Krane V, Marz W et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353: 238–248 [published erratum appears in N Engl J Med 2005; 353: 1640].
see original article on page 814
Hypertension in connexin40-null mice: a renin disorder DC Spray1 Studies described in this issue indicate that the gap junction protein connexin40 (Cx40) appears to play an unexpected role in blood pressure regulation. In mice lacking this gap junction protein, renin secretion is high and not regulated by arteriolar pressure. Kidney International (2007) 72, 781–782. doi:10.1038/sj.ki.5002515
Gap junction channels uniquely fulfill the vital role of providing a pathway for intercellular diffusion of ions and small molecules between coupled cell populations within a tissue. In chordates, these channels are formed by connexin proteins, a family of about 20 members in mammals, where expression of isoforms is cell type and tissue specific, with some overlap. The biophysical properties of channels formed by individual connexins vary, as do those of proteins that bind to the connexins; this presumably confers differences tuned to match the function that these channels serve in various tissues, such as second messenger exchange in the liver and perhaps astrocytes in the brain, electrical signal propagation in excitable systems such as the heart, brain, and 1Dominick P. Purpura Department of Neuroscience,
Albert Einstein College of Medicine, Bronx, New York, USA Correspondence: DC Spray, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, New York 10461, USA. E-mail: [email protected]
pancreatic islet, and metabolite exchange in the lens. Because of the tissue-specific distribution of connexins and the well-known exchange of ions and signaling molecules through them, connexin-null mice might have been expected to have well-predicted and perhaps quite restricted phenotypes. For example, the ventricles of mice lacking connexin43 (Cx43) might be expected to beat arrhythmically because of loss of the most abundant gap junction protein, the liver of Cx32-null mice might be dysfunctional because of lack of signaling between periportal and perivenous hepatocytes, and Cx50 knockouts might be expected to display cataracts. In fact, although these changes are seen to one extent or another as part of the overall mouse phenotype, the major changes in the animals are different, revealing hitherto unsuspected (and to some degree still not well understood) roles of the individual connexins in the animal. Cx43-null mice die at birth as a result of congenital malformation in the right ventricle, blocking outflow to the lung; Cx32-null mice display reduced peripheral myelination (now known to be the genetic 781
co mmentar y
Figure 1 | Schematic diagram of distribution of Cx40 gap junction channels between cells of the juxtaglomerular apparatus. Smooth muscle and endothelial cells of the afferent arteriole are probably coupled to each other (dark lines connecting cells) and to interconnected renin-secreting cells (RSCs; blue cells in diagram). The downward arrow indicates regulation of renin release through factors released from the macula densa; the upward arrow indicates regulation of renin secretion by hemodynamic sensing. In the Cx40-null mouse, the connections among RSCs are lost, as are those between RSCs and endothelium, and RSCs are more numerous, causing increased basal renin release and disruption of normal hemodynamic sensing by RSCs in the vessel wall. (Adapted from ref. 5.)
basis of X-linked Charcot-Marie-Tooth disease); and Cx50-null mice show depressed lens development, although Cx50-null lenses do display opacification. Cx40 is the major gap junction protein of the cardiac atrium, and it was therefore not surprising that atrial conduction was slowed in the initial studies (for recent review see Severs et al.1). However, endothelial cells also express Cx40, and it was soon reported that Cx40-null mice were hypertensive, with the hypertension initially attributed to hemodynamic adaptations in the vascular wall.2 However, reports quickly appeared suggesting an association between renin secretion and connexin expression (for references, see Krattinger et al.3), and what remained for a definitive conclusion regarding cause was to examine renin secretion and distribution of renin-secreting cells in the juxtaglomerular apparatus of Cx40-null mice. Such studies have now been performed, published virtually simultaneously in three reports from two laboratories,3–5 including the report by Krattinger et al. in this issue of Kidney International.3 Both groups have now reported that Cx40-null mice are hypertensive as compared with either wild types or heterozygotes, and that both synthesis and plasma levels of renin are elevated, all of which are reversible by treatment with antagonists of angiotensin II or its converting enzyme.3,4 These effects are associated with increased 782
number of renin-secreting cells3,5 as well as altered distribution of the renin-secreting cells in the afferent arteriole5 (Figure 1). Studies on the 2K1C and high-salt models of renin-dependent hypertension3,5 as well as β-adrenergic stimulation4 further revealed that the major dysregulation was primarily, though not entirely, in signaling local blood flow in the afferent arteriole. Moreover, application of a gap junction blocker to perfused kidney showed a lack of pressure-induced secretion similar to that in the Cx40-nulls.4 These studies both reveal new roles of connexins in tissue function and raise questions that are central to understanding these roles. First, the findings provide further evidence that function of both endocrine and exocrine secretory cell populations relies on gap junction expression and that these cells are quite vulnerable targets of altered gap junction gene expression (for review see Michon et al.6). Second, there is the issue of why heterozygotes, in which cells express half the normal Cx40 levels, are normotensive and show normal levels of plasma renin. Does this reflect a threshold for the connexin gene dosage or for the ionic, metabolic, or second messenger coupling that the gap junction channels provide, and what role does such a threshold play in the secretory function of the cells? Third is the general question of whether the studied phenotype in a connexin knockout represents the
impact of lost intercellular communication itself, developmental compensation for either the loss of gap junction channels or non-channel-related functions, or altered expression of other genes through expression interlinkage or even congenic effects of the transgene.7–9 Answering such questions is central to understanding both global and tissue/cellular-level phenotypes of not only connexin knockouts, but other transgenics as well. That a number of mechanistic questions are raised by these papers definitively showing that hypertension in Cx40-null mice is due to deficient sensing of vascular hemodynamics illustrates both excitement and challenges presented by systems analysis of molecular function. Nevertheless, as Krattinger et al.3 point out, the Cx40-null mouse appears to provide a robust animal model for renindependent hypertension and thus may serve as a very useful model of the human disease. Moreover, induction of renindependent hypertension in the Cx40-null mouse further suggests that mutations or polymorphisms in this gap junction gene might be useful markers for hypertension in the human population. ACKNOWLEDGMENTS Research of the author’s laboratory is supported by grants from the National Institutes of Health. REFERENCES 1. 2.
3. 4. 5.
6. 7.
8.
9.
Severs NJ, Dupont E, Thomas N et al. Alterations in cardiac connexin expression in cardiomyopathies. Adv Cardiol 2006; 42: 228–242. de Wit C, Wolfle SE, Hopfl B. Connexin-dependent communication within the vascular wall: contribution to the control of arteriolar diameter. Adv Cardiol 2006; 42: 268–283. Krattinger N, Capponi A, Mazzolai L et al. Connexin40 regulates renin production and blood pressure. Kidney Int 2007; 72: 814–822. Wagner C, de Wit C, Kurtz L et al. Connexin40 is essential for the pressure control of renin synthesis and secretion. Circ Res 2007; 100: 556–563. Kurtz L, Schweda F, de Wit C et al. Lack of connexin 40 causes displacement of renin-producing cells from afferent arterioles to the extraglomerular mesangium. J Am Soc Nephrol 2007; 18: 1103–1011. Michon L, Nlend Nlend R, Bavamian S et al. Involvement of gap junctional communication in secretion. Biochim Biophys Acta 2005; 1719: 82–101. Insel PA, Patel HH. Do studies in caveolin-knockouts teach us about physiology and pharmacology or instead, the ways mice compensate for ‘lost proteins’? Br J Pharmacol 2007; 150: 251–254. Iacobas DA, Iacobas S, Spray DC. Connexindependent transcellular transcriptomic networks in mouse brain. Prog Biophys Mol Biol 2007; 94: 169–185. Schalkwyk LC, Fernandes C, Nash MW et al. Interpretation of knockout experiments: the congenic footprint. Genes Brain Behav 2007; 6: 299–303. Kidney International (2007) 72
2.
3.
4.
5.
6.
7.
8.
9. 10.
11.
12.
13. 14.
15.
16.
17.
18.
Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA. Division of Kidney, Urologic, and Hematologic Diseases Annual, Data Report 2005, pp128–129. Go AS, Chertow GM, Fan D et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 1296–1305. Lowrie EG, Lew NL. Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 1990; 15: 458–482. Iseki K, Yamazato M, Tozawa M, Takishita S. Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients. Kidney Int 2002; 61: 1887–1893. Stompor T, Pasowicz M, Sullowicz W et al. An association between coronary artery calcification score, lipid profile, and selected markers of chronic inflammation in ESRD patients treated with peritoneal dialysis. Am J Kidney Dis 2003; 41: 203–211. Shoji T, Nishizawa Y, Kawagishi T et al. Intermediatedensity lipoprotein as an independent risk factor for aortic atherosclerosis in hemodialysis patients. J Am Soc Nephrol 1998; 9: 1277–1284. Koch M, Kutkuhn B, Grabensee B, Ritz E. Apolipoprotein A, fibrinogen, age, and history of stroke are predictors of death in dialysed diabetic patients: a prospective study in 412 subjects. Nephrol Dial Transplant 1997; 12: 2603–2611. Okubo K, Ikewaki K, Sakai S et al. Abnormal HDL apolipoprotein A-I and A-II kinetics in hemodialysis patients: a stable isotope study. J Am Soc Nephrol 2004; 15: 1008–1015. Kaysen GA. Disorders in high-density metabolism with insulin resistance and chronic kidney disease. J Ren Nutr 2007; 17: 4–8. Ikewaki K, Schaefer JR, Frischmann ME et al. Delayed in vivo catabolism of intermediatedensity lipoprotein and low-density lipoprotein in hemodialysis patients as potential cause of premature atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25: 2615–2622. Walzem RL, Watkins S, Frankel EN et al. Older plasma lipoproteins are more susceptible to oxidation: a linking mechanism for the lipid and oxidation theories of atherosclerotic cardiovascular disease. Proc Natl Acad Sci USA 1995; 92: 7460–7464. Chan MK, Persaud J, Varghese Z, Moorhead JF. Pathogenic roles of post-heparin lipases in lipid abnormalities in hemodialysis patients. Kidney Int 1984; 25: 812–818. Kim C, Vaziri ND. Down-regulation of hepatic LDL receptor-related protein (LRP) in chronic renal failure. Kidney Int 2005; 67: 1028–1032. Lee DM, Knight-Gibson C, Samuelsson O et al. Lipoprotein particle abnormalities and the impaired lipolysis in renal insufficiency. Kidney Int 2002; 61: 209–218. Dautin G, Soltani Z, Ducloux D et al. Hemodialysis reduces plasma apolipoprotein C-I concentration making VLDL a better substrate for lipoprotein lipase. Kidney Int 2007; 72: 871–878. Swaney JB, Weisgraber KH. Effect of apolipoprotein C-I peptides on the apolipoprotein E content and receptor-binding properties of beta-migrating very low density lipoproteins. J Lipid Res 1994; 35: 134–142. van der Hoogt CC, Berbee JF, Espirito et al. Apolipoprotein CI causes hypertriglyceridemia independent of the very-low-density lipoprotein receptor and apolipoprotein CIII in mice. Biochim Biophys Acta 2006; 1761: 213–220. Berbee JF, van der Hoogt CC, Sundararaman D et
Kidney International (2007) 72
al. Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL. J Lipid Res 2005; 46: 297–306. 19. Mekki K, Bouchenak M, Remaoun M, Belleville JL. Effect of long-term hemodialysis on plasma lecithin: cholesterol acyltransferase activity and the amounts and compositions of HDL2 and HDL3 in hemodialysis-treated patients with chronic renal failure. A 9-year longitudinal study. Med Sci Monit 2004; 10: CR439–CR446. 20. Dumont L, Gautier T, de Barros JP et al. Molecular mechanism of the blockade of plasma cholesteryl ester transfer protein by its physiological inhibitor apolipoprotein CI. J Biol Chem 2005; 280: 38108–38116.
21. Bondarenko PV, Cockrill SL, Watkins LK et al. Mass spectral study of polymorphism of the apolipoproteins of very low density lipoprotein. J Lipid Res 1999; 40: 543–555. 22. Swaney JB, Weisgraber KH. Effect of apolipoprotein C-I peptides on the apolipoprotein E content and receptor-binding properties of beta-migrating very low density lipoproteins. J Lipid Res 1994; 35: 134–142. 23. Wanner C, Krane V, Marz W et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353: 238–248 [published erratum appears in N Engl J Med 2005; 353: 1640].
see original article on page 814
Hypertension in connexin40-null mice: a renin disorder DC Spray1 Studies described in this issue indicate that the gap junction protein connexin40 (Cx40) appears to play an unexpected role in blood pressure regulation. In mice lacking this gap junction protein, renin secretion is high and not regulated by arteriolar pressure. Kidney International (2007) 72, 781–782. doi:10.1038/sj.ki.5002515
Gap junction channels uniquely fulfill the vital role of providing a pathway for intercellular diffusion of ions and small molecules between coupled cell populations within a tissue. In chordates, these channels are formed by connexin proteins, a family of about 20 members in mammals, where expression of isoforms is cell type and tissue specific, with some overlap. The biophysical properties of channels formed by individual connexins vary, as do those of proteins that bind to the connexins; this presumably confers differences tuned to match the function that these channels serve in various tissues, such as second messenger exchange in the liver and perhaps astrocytes in the brain, electrical signal propagation in excitable systems such as the heart, brain, and 1Dominick P. Purpura Department of Neuroscience,
Albert Einstein College of Medicine, Bronx, New York, USA Correspondence: DC Spray, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx, New York 10461, USA. E-mail: [email protected]
pancreatic islet, and metabolite exchange in the lens. Because of the tissue-specific distribution of connexins and the well-known exchange of ions and signaling molecules through them, connexin-null mice might have been expected to have well-predicted and perhaps quite restricted phenotypes. For example, the ventricles of mice lacking connexin43 (Cx43) might be expected to beat arrhythmically because of loss of the most abundant gap junction protein, the liver of Cx32-null mice might be dysfunctional because of lack of signaling between periportal and perivenous hepatocytes, and Cx50 knockouts might be expected to display cataracts. In fact, although these changes are seen to one extent or another as part of the overall mouse phenotype, the major changes in the animals are different, revealing hitherto unsuspected (and to some degree still not well understood) roles of the individual connexins in the animal. Cx43-null mice die at birth as a result of congenital malformation in the right ventricle, blocking outflow to the lung; Cx32-null mice display reduced peripheral myelination (now known to be the genetic 781
co mmentar y
Figure 1 | Schematic diagram of distribution of Cx40 gap junction channels between cells of the juxtaglomerular apparatus. Smooth muscle and endothelial cells of the afferent arteriole are probably coupled to each other (dark lines connecting cells) and to interconnected renin-secreting cells (RSCs; blue cells in diagram). The downward arrow indicates regulation of renin release through factors released from the macula densa; the upward arrow indicates regulation of renin secretion by hemodynamic sensing. In the Cx40-null mouse, the connections among RSCs are lost, as are those between RSCs and endothelium, and RSCs are more numerous, causing increased basal renin release and disruption of normal hemodynamic sensing by RSCs in the vessel wall. (Adapted from ref. 5.)
basis of X-linked Charcot-Marie-Tooth disease); and Cx50-null mice show depressed lens development, although Cx50-null lenses do display opacification. Cx40 is the major gap junction protein of the cardiac atrium, and it was therefore not surprising that atrial conduction was slowed in the initial studies (for recent review see Severs et al.1). However, endothelial cells also express Cx40, and it was soon reported that Cx40-null mice were hypertensive, with the hypertension initially attributed to hemodynamic adaptations in the vascular wall.2 However, reports quickly appeared suggesting an association between renin secretion and connexin expression (for references, see Krattinger et al.3), and what remained for a definitive conclusion regarding cause was to examine renin secretion and distribution of renin-secreting cells in the juxtaglomerular apparatus of Cx40-null mice. Such studies have now been performed, published virtually simultaneously in three reports from two laboratories,3–5 including the report by Krattinger et al. in this issue of Kidney International.3 Both groups have now reported that Cx40-null mice are hypertensive as compared with either wild types or heterozygotes, and that both synthesis and plasma levels of renin are elevated, all of which are reversible by treatment with antagonists of angiotensin II or its converting enzyme.3,4 These effects are associated with increased 782
number of renin-secreting cells3,5 as well as altered distribution of the renin-secreting cells in the afferent arteriole5 (Figure 1). Studies on the 2K1C and high-salt models of renin-dependent hypertension3,5 as well as β-adrenergic stimulation4 further revealed that the major dysregulation was primarily, though not entirely, in signaling local blood flow in the afferent arteriole. Moreover, application of a gap junction blocker to perfused kidney showed a lack of pressure-induced secretion similar to that in the Cx40-nulls.4 These studies both reveal new roles of connexins in tissue function and raise questions that are central to understanding these roles. First, the findings provide further evidence that function of both endocrine and exocrine secretory cell populations relies on gap junction expression and that these cells are quite vulnerable targets of altered gap junction gene expression (for review see Michon et al.6). Second, there is the issue of why heterozygotes, in which cells express half the normal Cx40 levels, are normotensive and show normal levels of plasma renin. Does this reflect a threshold for the connexin gene dosage or for the ionic, metabolic, or second messenger coupling that the gap junction channels provide, and what role does such a threshold play in the secretory function of the cells? Third is the general question of whether the studied phenotype in a connexin knockout represents the
impact of lost intercellular communication itself, developmental compensation for either the loss of gap junction channels or non-channel-related functions, or altered expression of other genes through expression interlinkage or even congenic effects of the transgene.7–9 Answering such questions is central to understanding both global and tissue/cellular-level phenotypes of not only connexin knockouts, but other transgenics as well. That a number of mechanistic questions are raised by these papers definitively showing that hypertension in Cx40-null mice is due to deficient sensing of vascular hemodynamics illustrates both excitement and challenges presented by systems analysis of molecular function. Nevertheless, as Krattinger et al.3 point out, the Cx40-null mouse appears to provide a robust animal model for renindependent hypertension and thus may serve as a very useful model of the human disease. Moreover, induction of renindependent hypertension in the Cx40-null mouse further suggests that mutations or polymorphisms in this gap junction gene might be useful markers for hypertension in the human population. ACKNOWLEDGMENTS Research of the author’s laboratory is supported by grants from the National Institutes of Health. REFERENCES 1. 2.
3. 4. 5.
6. 7.
8.
9.
Severs NJ, Dupont E, Thomas N et al. Alterations in cardiac connexin expression in cardiomyopathies. Adv Cardiol 2006; 42: 228–242. de Wit C, Wolfle SE, Hopfl B. Connexin-dependent communication within the vascular wall: contribution to the control of arteriolar diameter. Adv Cardiol 2006; 42: 268–283. Krattinger N, Capponi A, Mazzolai L et al. Connexin40 regulates renin production and blood pressure. Kidney Int 2007; 72: 814–822. Wagner C, de Wit C, Kurtz L et al. Connexin40 is essential for the pressure control of renin synthesis and secretion. Circ Res 2007; 100: 556–563. Kurtz L, Schweda F, de Wit C et al. Lack of connexin 40 causes displacement of renin-producing cells from afferent arterioles to the extraglomerular mesangium. J Am Soc Nephrol 2007; 18: 1103–1011. Michon L, Nlend Nlend R, Bavamian S et al. Involvement of gap junctional communication in secretion. Biochim Biophys Acta 2005; 1719: 82–101. Insel PA, Patel HH. Do studies in caveolin-knockouts teach us about physiology and pharmacology or instead, the ways mice compensate for ‘lost proteins’? Br J Pharmacol 2007; 150: 251–254. Iacobas DA, Iacobas S, Spray DC. Connexindependent transcellular transcriptomic networks in mouse brain. Prog Biophys Mol Biol 2007; 94: 169–185. Schalkwyk LC, Fernandes C, Nash MW et al. Interpretation of knockout experiments: the congenic footprint. Genes Brain Behav 2007; 6: 299–303. Kidney International (2007) 72