Available online at www.sciencedirect.com
ScienceDirect Editorial overview: Cardiovascular and renal: Blood pressure regulation and hypertension — hunt for new treatment targets in the kidneys Pernille BL Hansen and Boye L Jensen Current Opinion in Pharmacology 2015, 21:v–viii For a complete overview see the Issue Available online 25th February 2015 http://dx.doi.org/10.1016/j.coph.2015.02.005 1471-4892/# 2015 Elsevier Ltd. All rights reserved.
Pernille BL Hansen
Boye L Jensen
Cardiovascular and Renal Research, University of Southern Denmark, DK-5000 Odense, Denmark e-mail: [email protected] Pernille BL Hansen is Professor of Translational Cardiovascular and Renal Physiology at the University of Southern Denmark since 2013. Her research interests are vascular and renal function both in normal physiological settings and in cardiovascular disease. A major aim is to determine the importance of T-type calcium channels in human tissue and mouse models. Furthermore, she investigates aldosterone effects on human and mouse blood vessels and the involvement in blood pressure regulation. Boye L Jensen is MD and Professor of Physiology at the University of Southern Denmark since 2011. His research effort is devoted to the understanding of hypertension pathogenesis in situations with microalbuminuria/proteinuria, for example,
www.sciencedirect.com
According to the World Health Organization, raised blood pressure is responsible for 12% of all deaths. A recent population study showed that 25% of adult Chinese suffer from hypertension, the trend is increasing. Increased blood pressure is a leading risk factor for heart, kidney and vascular disease including stroke. Management of increased blood pressure consumes an estimated 10% of overall healthcare expenditures globally. Pathogenesis is multifactorial involving both genetic and lifestyle factors. First line pharmacological treatment is directed towards promoting renal sodium excretion (diuretics) and/or antagonism of endogenous systems that support sodium retention (renin–angiotensin–aldosterone system, sympathetic nerve activity). Because blood pressure ‘follows the kidney’ in classical animal transplantation experiments and the last decades have revealed that a range monogenic diseases with gain-of function mutations associated with hypertension involve renal electrolyte, notably sodium, transport proteins, attention on the kidneys is warranted. In the current issue we have focused on the involvement of kidneys in blood pressure homeostasis and in hypertension. A range of global experts in the field of cardiovascular and renal physiology, clinical medicine and pharmacology have contributed. We have chosen to cover a spectrum of effectors/targets in blood pressure control and wherever possible, new treatments are critically discussed. The special issue can be thematically divided into subsections that we briefly highlight below. First, kidney-dependent mechanisms causing elevated blood pressure are presented. The significant hypertension associated with ‘displaced’ renal renin-producing cells in mice with functional deletion of gap junction protein connexin 40 is a ground-breaking discovery. A known clinical hypertensive counterpart is described with loss of function mutations in connexin 40 and Armin Kurtz discusses the observation that renin release from displaced, ectopic renin-producing cells in the glomerular tuft area escapes negative pressure control [1]. The observation has wide implications, since a few displaced renin-cells in an adult kidney in principle would suffice to evoke hypertension. A new discovery with therapeutical consequences was made when the functionally well-characterized, but for decades molecularly unknown, vascular calciumactivated chloride current was identified as TMEM16a or anoctamin, which is a dominant contributor to agonist-induced depolarization and contraction in arteriolar smooth muscle. Its targeted vascular deletion leads to lower blood pressure [2]. Thus, the channel appears to be ready for pharmacological antihypertensive targeting and is reviewed by Aalkjaer et al. In this section of new mechanisms, we categorize the discovery in patients with malignant disease of acute hypertension shortly after the administration of Current Opinion in Pharmacology 2015, 21:v–viii
vi Cardiovascular and renal
preeclampsia or diabetic nephropathy, with special emphasis on the epithelial sodium channel ENaC and proteases in urine. Moreover, control of renin release has been a focus point. The research combines human translational studies and studies in mice with targeted gene deletions.
antagonists of vascular endothelial growth factor (VEGF) and other growth factors by antibodies or small molecule receptor tyrosine kinase inhibitors. For peptide growth factors believed to have primarily a paracrine action, it was a surprise to discover this marked, adverse, systemic hypertensive effect of antagonists Von den Meiracker et al. provides a review of etiology behind the hypertension and its use as a ‘positive’ biomarker for the anti-cancer responsiveness to the treatment. Another discovery which has changed our understanding of hypertension is the involvement of the immune system. The review by Zhang and Crowley describes how T lymphocytes and the immune system contribute to the pathogenesis of hypertension. T lymphocytes raise blood pressure by causing vascular dysfunction and sodium retention as they infiltrate the kidney and especially the renal blood vessels during hypertension. Furthermore, mice lacking functional T lymphocytes seem to be protected from hypertension. The final contribution in this area is by Singh and Denton who reviews fetally programmed hypertension that is thought to involve the kidney. Low birth weight and impaired development predisposes the individual to hypertension in adult life. Both genetic and environmental factors affect the development of the kidney and low numbers of nephrons is associated with hypertension. The author suggests surveillance of children born of low birth weight for the early identification of disease and counseling with respect to controlling salt intake. The next section is on renal paracrine factors with impact on blood pressure. Endothelin antagonists are in clinical use and Erika Boesen reviews what is known about the mechanisms whereby endothelin receptors in the kidney affect blood pressure. This appears at least partially to be mediated through renal epithelial action and regulation of salt and water homeostasis. Renal prostaglandins are important for support of renal function during neurohumoral activation as occurs after, for example, dehydration of diuretic treatment. Inhibitors of prostaglandin formation, typically non-steroidal anti-inflammatory drugs, may lead to decrease in renal function and ultimately to renal failure and often elicit blood pressure increase. The inducible isoform of cyclooxygenase, COX-2, is expressed constitutively at very few sites in the normal organism and the kidney is one of them. An exciting new interplay has been revealed whereby Angiotensin II-mediated hypertension evokes a vicious cycle in the renal medulla between proreninreceptor (PRR) and COX-2 activity. This is reviewed by Tianxin Yang. The final contribution in this subsection is on the important paracrine factor ATP, released abundantly from the renal epithelium — particularly the collecting duct, and with its receptors that appear also to contribute importantly to arterial pressure and hypertension. Purinergic P2 receptors play a critical role for regulation of renal vascular resistance and tubular reabsorption. Van Beusecum and Inscho highlight recent discoveries in the field of purinergic signalling. In a subsection on new antihypertensive treatments with specific focus on the kidney, the invasive antihypertensive interventions of catheter-based radiofrequency renal sympathetic nerve ablation — ‘renal denervation’ — and device-drive baroreceptor stimulation, ‘barostim’ therapy are discussed. Kjeldsen’s groups from Oslo provide a critical overview of current status on renal denervation including patient selection criteria, control groups, efficacy and perspective for the intervention with emphasis on data from the three symplicity trials and several other intervention trials. An antihypertensive invasive device-based intervention that appears to undergo a revival is ‘barostim’ or exogenous baroreflex stimulation which, among other issues, is covered in the review by Laffin and Bakris. This review addresses possible treatments of hypertensive individuals in whom
Current Opinion in Pharmacology 2015, 21:v–viii
www.sciencedirect.com
Editorial overview Hansen and Jensen vii
sympathetic drive contributes to blood pressure elevation. The review highlights recent clinical trial results of renal denervation therapy and baroreflex activation therapy. The review clarifies and discusses the promise of baroreflex activation therapy. Together, the two reviews by Laffin and Bakris and by Kjeldsen et al. emphasize the importance of the sympathetic nervous system in the etiology of hypertension. A new promising pharmacological treatment that falls within the nitric oxide/cGMP pathway is direct stimulation of the soluble guanylyl cyclase enzyme. Direct agonists of this enzyme are now registered for treatment of pulmonary hypertension and hold promising potential in treatment of arterial hypertension and also in protection from end-organ damage independent of pressure which is very relevant for kidneys since there are currently no interventions the can halt or reverse kidney fibrosis. A detailed review with extensive tables is provided by Stasch et al. Much new information has emerged for the longest known humoral system that controls renal salt excretion, extracellular volume and blood pressure, the renin-angiotensin-aldosterone system which is treated in the next subsection. Insight has increased significantly in 3 areas over the last decades: firstly, the application of genetic manipulation in experimental animals, notably mice, has given much new insight in the function of key players; secondly, the discovery of new arms (AT2 receptor, Mas receptor, ACE2 and prorenin receptors and thirdly, the tedious development of new drugs and their clinical testing (renin inhibitors, AT2 agonists). The special issue contains a review on agonists and effect of agonism for the AT2 receptor in long term organ protection or even reversal of cardiovascular end organ injury (fibrosis, atherosclerosis) Muscha Steckelings et al. provide an overview of potential organ systems where beneficial actions are predicted and on the ongoing trials. The exact opposite, injurious, long term effects of ANGII are believed to be predominantly associated with the AT1 receptor. A series of elegant knock out studies and cross transplantation studies in mice have revealed the crucial role for the kidney for maintained hypertension after ANGII infusion in contrast to heart and vessels [3]. Furthermore, the renal epithelial segments that contribute this effect of ANGII-AT1 interaction have been mapped and direct trophic actions versus pressure-related action of ANGII on heart and vessels are all being reviewed by Chen and Coffman. The intracellular machinery that determines cell surface association and internalization of ANGII-AT1 receptor consists of specific regulating proteins. It turns out, that deletion of the ANGII-receptor regulating protein Atrap has consequences for blood pressure and its functional significance is reviewed by Hayo Castrop with special focus on angiotensin II-dependent volume homoeostasis and vascular resistance. The controversy of the role played by systemic generation of angiotensin II versus the local generation of www.sciencedirect.com
angiotensin II within kidney and the relative importance for hypertension is discussed in the review by Bernstein et al. It is clear that intrarenal angiotensin converting enzyme, ACE, plays an important role in experimental animal models of hypertension as mice lacking only renal ACE are protected against hypertension [4]. The intrarenal angiotensin II production and local regulation of renal sodium transporters represents a new understanding of the mechanism underlying inappropriate regulation of salt and water balance. However, now the real question is what role the intrarenal RAS plays in humans. ANG II is only one of the effector molecules in the system and what is the distinct role for aldosterone, the mineralocorticoid steroid effector in the renin cascade whose synthesis and release is stimulated by ANGII? New insight demonstrate significant direct actions of aldosterone-MR interaction in vessels and MR within smooth muscles are involved in blood pressure regulation [5]. Jaisser et al. review findings on the vascular smooth muscle and endothelial cells in response to aldosterone which proves to be an exciting new avenue. The aldosterone field is further discussed by Lenzini and Rossi who focuses on hyperaldosteronism; an underdiagnosed condition with high aldosterone level despite high blood pressure, sodium retention, suppression of the renin angiotensin system and low potassium levels. The review focuses on gene mutations in potassium and calcium channels involved in the pathogenesis of adrenal aldosterone overproduction and the authors suggests a novel clinical molecular classification of primary hyperaldosteronism as a channelopathy. Following the section on renin–angiotensins system and finishing the special issue are two reviews highlighting the interaction of the renin–angiotensin–aldosterone system with the hypothalamic–pituitary axis through enzymatic control of local tissue glucocorticoid and mineralocorticoid hormone concentrations and the renal epithelial electrolyte transport proteins in the distal nephron and collecting duct segments which are targets for hormonal control and impact blood pressure. The adrenal mineralocorticoid and glucocorticoid hormone tissue and thus target cell concentrations are controlled not only by rate of synthesis and release but also by enzymes expressed locally in the tissues. Compared to the 11betahydroxysteroid dehydrogenase type II that ‘protects’ the mineralocorticoid receptor from illicit activation by glucocorticoids, the significance of 11bHSD-1 is less well characterized. 11bHSD-1 may generate active glucocorticoid locally in tissues of significance for blood pressure control. Hunter and Bailey present a review of current status of knowledge with comprehensive tables regarding significance of the 11bHSD-1 and 11bHSD-2 enzymes in blood pressure regulation. The discovery of rare loss-offunction mutations in the aldosterone-sensitive renal Na+ transport molecules and their intracellular controllers have shown that impaired renal sodium excretion is Current Opinion in Pharmacology 2015, 21:v–viii
viii Cardiovascular and renal
sufficient for a low-renin, salt-sensitive, pseudo-hyperaldosteronism-type of hypertension. This discovery was seminal to establish beyond reasonable doubt a primary role for renal sodium transport in blood pressure control and as a pathogenic factor in hypertension. Hummler et al. give an extensive update of knowledge on systemic and molecular control of the two Na+ transporters in the distal nephron that are specifically relevant in this context, the thiazide-sensitive Na-Cl contransporter NCC and the epithelial sodium channel ENaC. Comprehensive tables provide an in-depth overview of current status of knowledge and should be a powerful aid for interested readers. It should be obvious that the present issue contains a wealth of information on progress in target identification and pharmacological and device-based treatments for arterial hypertension directed against the kidney based on new mechanistic insight and technical innovations. We would like to thank the authors for their excellent contributions and we wish the readers a pleasant journey with
Current Opinion in Pharmacology 2015, 21:v–viii
the articles and hope the issue may inspire discussion, development of ideas and new lines of research that may benefit patients.
Conflict of interest statement Nothing declared.
References 1.
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.
2.
Heinze C, Seniuk A, Sokolov MV et al.: Disruption of vascular Ca2+-activated chloride currents lowers blood pressure. J Clin Invest 2014, 124:675-686.
3.
Crowley SD, Gurley SB, Oliverio MI et al.: Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system. J Clin Invest 2005:1092-1099.
4.
Gonzalez-Villalobos RA, Janjoulia T, Fletcher NK et al.: The absence of intrarenal ACE protects against hypertension. J Clin Invest 2013, 123(5):2011-2023.
5.
McCurley A, Pires PW, Bender SB et al.: Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med 2012, 9:1429-1433.
www.sciencedirect.com
ScienceDirect Editorial overview: Cardiovascular and renal: Blood pressure regulation and hypertension — hunt for new treatment targets in the kidneys Pernille BL Hansen and Boye L Jensen Current Opinion in Pharmacology 2015, 21:v–viii For a complete overview see the Issue Available online 25th February 2015 http://dx.doi.org/10.1016/j.coph.2015.02.005 1471-4892/# 2015 Elsevier Ltd. All rights reserved.
Pernille BL Hansen
Boye L Jensen
Cardiovascular and Renal Research, University of Southern Denmark, DK-5000 Odense, Denmark e-mail: [email protected] Pernille BL Hansen is Professor of Translational Cardiovascular and Renal Physiology at the University of Southern Denmark since 2013. Her research interests are vascular and renal function both in normal physiological settings and in cardiovascular disease. A major aim is to determine the importance of T-type calcium channels in human tissue and mouse models. Furthermore, she investigates aldosterone effects on human and mouse blood vessels and the involvement in blood pressure regulation. Boye L Jensen is MD and Professor of Physiology at the University of Southern Denmark since 2011. His research effort is devoted to the understanding of hypertension pathogenesis in situations with microalbuminuria/proteinuria, for example,
www.sciencedirect.com
According to the World Health Organization, raised blood pressure is responsible for 12% of all deaths. A recent population study showed that 25% of adult Chinese suffer from hypertension, the trend is increasing. Increased blood pressure is a leading risk factor for heart, kidney and vascular disease including stroke. Management of increased blood pressure consumes an estimated 10% of overall healthcare expenditures globally. Pathogenesis is multifactorial involving both genetic and lifestyle factors. First line pharmacological treatment is directed towards promoting renal sodium excretion (diuretics) and/or antagonism of endogenous systems that support sodium retention (renin–angiotensin–aldosterone system, sympathetic nerve activity). Because blood pressure ‘follows the kidney’ in classical animal transplantation experiments and the last decades have revealed that a range monogenic diseases with gain-of function mutations associated with hypertension involve renal electrolyte, notably sodium, transport proteins, attention on the kidneys is warranted. In the current issue we have focused on the involvement of kidneys in blood pressure homeostasis and in hypertension. A range of global experts in the field of cardiovascular and renal physiology, clinical medicine and pharmacology have contributed. We have chosen to cover a spectrum of effectors/targets in blood pressure control and wherever possible, new treatments are critically discussed. The special issue can be thematically divided into subsections that we briefly highlight below. First, kidney-dependent mechanisms causing elevated blood pressure are presented. The significant hypertension associated with ‘displaced’ renal renin-producing cells in mice with functional deletion of gap junction protein connexin 40 is a ground-breaking discovery. A known clinical hypertensive counterpart is described with loss of function mutations in connexin 40 and Armin Kurtz discusses the observation that renin release from displaced, ectopic renin-producing cells in the glomerular tuft area escapes negative pressure control [1]. The observation has wide implications, since a few displaced renin-cells in an adult kidney in principle would suffice to evoke hypertension. A new discovery with therapeutical consequences was made when the functionally well-characterized, but for decades molecularly unknown, vascular calciumactivated chloride current was identified as TMEM16a or anoctamin, which is a dominant contributor to agonist-induced depolarization and contraction in arteriolar smooth muscle. Its targeted vascular deletion leads to lower blood pressure [2]. Thus, the channel appears to be ready for pharmacological antihypertensive targeting and is reviewed by Aalkjaer et al. In this section of new mechanisms, we categorize the discovery in patients with malignant disease of acute hypertension shortly after the administration of Current Opinion in Pharmacology 2015, 21:v–viii
vi Cardiovascular and renal
preeclampsia or diabetic nephropathy, with special emphasis on the epithelial sodium channel ENaC and proteases in urine. Moreover, control of renin release has been a focus point. The research combines human translational studies and studies in mice with targeted gene deletions.
antagonists of vascular endothelial growth factor (VEGF) and other growth factors by antibodies or small molecule receptor tyrosine kinase inhibitors. For peptide growth factors believed to have primarily a paracrine action, it was a surprise to discover this marked, adverse, systemic hypertensive effect of antagonists Von den Meiracker et al. provides a review of etiology behind the hypertension and its use as a ‘positive’ biomarker for the anti-cancer responsiveness to the treatment. Another discovery which has changed our understanding of hypertension is the involvement of the immune system. The review by Zhang and Crowley describes how T lymphocytes and the immune system contribute to the pathogenesis of hypertension. T lymphocytes raise blood pressure by causing vascular dysfunction and sodium retention as they infiltrate the kidney and especially the renal blood vessels during hypertension. Furthermore, mice lacking functional T lymphocytes seem to be protected from hypertension. The final contribution in this area is by Singh and Denton who reviews fetally programmed hypertension that is thought to involve the kidney. Low birth weight and impaired development predisposes the individual to hypertension in adult life. Both genetic and environmental factors affect the development of the kidney and low numbers of nephrons is associated with hypertension. The author suggests surveillance of children born of low birth weight for the early identification of disease and counseling with respect to controlling salt intake. The next section is on renal paracrine factors with impact on blood pressure. Endothelin antagonists are in clinical use and Erika Boesen reviews what is known about the mechanisms whereby endothelin receptors in the kidney affect blood pressure. This appears at least partially to be mediated through renal epithelial action and regulation of salt and water homeostasis. Renal prostaglandins are important for support of renal function during neurohumoral activation as occurs after, for example, dehydration of diuretic treatment. Inhibitors of prostaglandin formation, typically non-steroidal anti-inflammatory drugs, may lead to decrease in renal function and ultimately to renal failure and often elicit blood pressure increase. The inducible isoform of cyclooxygenase, COX-2, is expressed constitutively at very few sites in the normal organism and the kidney is one of them. An exciting new interplay has been revealed whereby Angiotensin II-mediated hypertension evokes a vicious cycle in the renal medulla between proreninreceptor (PRR) and COX-2 activity. This is reviewed by Tianxin Yang. The final contribution in this subsection is on the important paracrine factor ATP, released abundantly from the renal epithelium — particularly the collecting duct, and with its receptors that appear also to contribute importantly to arterial pressure and hypertension. Purinergic P2 receptors play a critical role for regulation of renal vascular resistance and tubular reabsorption. Van Beusecum and Inscho highlight recent discoveries in the field of purinergic signalling. In a subsection on new antihypertensive treatments with specific focus on the kidney, the invasive antihypertensive interventions of catheter-based radiofrequency renal sympathetic nerve ablation — ‘renal denervation’ — and device-drive baroreceptor stimulation, ‘barostim’ therapy are discussed. Kjeldsen’s groups from Oslo provide a critical overview of current status on renal denervation including patient selection criteria, control groups, efficacy and perspective for the intervention with emphasis on data from the three symplicity trials and several other intervention trials. An antihypertensive invasive device-based intervention that appears to undergo a revival is ‘barostim’ or exogenous baroreflex stimulation which, among other issues, is covered in the review by Laffin and Bakris. This review addresses possible treatments of hypertensive individuals in whom
Current Opinion in Pharmacology 2015, 21:v–viii
www.sciencedirect.com
Editorial overview Hansen and Jensen vii
sympathetic drive contributes to blood pressure elevation. The review highlights recent clinical trial results of renal denervation therapy and baroreflex activation therapy. The review clarifies and discusses the promise of baroreflex activation therapy. Together, the two reviews by Laffin and Bakris and by Kjeldsen et al. emphasize the importance of the sympathetic nervous system in the etiology of hypertension. A new promising pharmacological treatment that falls within the nitric oxide/cGMP pathway is direct stimulation of the soluble guanylyl cyclase enzyme. Direct agonists of this enzyme are now registered for treatment of pulmonary hypertension and hold promising potential in treatment of arterial hypertension and also in protection from end-organ damage independent of pressure which is very relevant for kidneys since there are currently no interventions the can halt or reverse kidney fibrosis. A detailed review with extensive tables is provided by Stasch et al. Much new information has emerged for the longest known humoral system that controls renal salt excretion, extracellular volume and blood pressure, the renin-angiotensin-aldosterone system which is treated in the next subsection. Insight has increased significantly in 3 areas over the last decades: firstly, the application of genetic manipulation in experimental animals, notably mice, has given much new insight in the function of key players; secondly, the discovery of new arms (AT2 receptor, Mas receptor, ACE2 and prorenin receptors and thirdly, the tedious development of new drugs and their clinical testing (renin inhibitors, AT2 agonists). The special issue contains a review on agonists and effect of agonism for the AT2 receptor in long term organ protection or even reversal of cardiovascular end organ injury (fibrosis, atherosclerosis) Muscha Steckelings et al. provide an overview of potential organ systems where beneficial actions are predicted and on the ongoing trials. The exact opposite, injurious, long term effects of ANGII are believed to be predominantly associated with the AT1 receptor. A series of elegant knock out studies and cross transplantation studies in mice have revealed the crucial role for the kidney for maintained hypertension after ANGII infusion in contrast to heart and vessels [3]. Furthermore, the renal epithelial segments that contribute this effect of ANGII-AT1 interaction have been mapped and direct trophic actions versus pressure-related action of ANGII on heart and vessels are all being reviewed by Chen and Coffman. The intracellular machinery that determines cell surface association and internalization of ANGII-AT1 receptor consists of specific regulating proteins. It turns out, that deletion of the ANGII-receptor regulating protein Atrap has consequences for blood pressure and its functional significance is reviewed by Hayo Castrop with special focus on angiotensin II-dependent volume homoeostasis and vascular resistance. The controversy of the role played by systemic generation of angiotensin II versus the local generation of www.sciencedirect.com
angiotensin II within kidney and the relative importance for hypertension is discussed in the review by Bernstein et al. It is clear that intrarenal angiotensin converting enzyme, ACE, plays an important role in experimental animal models of hypertension as mice lacking only renal ACE are protected against hypertension [4]. The intrarenal angiotensin II production and local regulation of renal sodium transporters represents a new understanding of the mechanism underlying inappropriate regulation of salt and water balance. However, now the real question is what role the intrarenal RAS plays in humans. ANG II is only one of the effector molecules in the system and what is the distinct role for aldosterone, the mineralocorticoid steroid effector in the renin cascade whose synthesis and release is stimulated by ANGII? New insight demonstrate significant direct actions of aldosterone-MR interaction in vessels and MR within smooth muscles are involved in blood pressure regulation [5]. Jaisser et al. review findings on the vascular smooth muscle and endothelial cells in response to aldosterone which proves to be an exciting new avenue. The aldosterone field is further discussed by Lenzini and Rossi who focuses on hyperaldosteronism; an underdiagnosed condition with high aldosterone level despite high blood pressure, sodium retention, suppression of the renin angiotensin system and low potassium levels. The review focuses on gene mutations in potassium and calcium channels involved in the pathogenesis of adrenal aldosterone overproduction and the authors suggests a novel clinical molecular classification of primary hyperaldosteronism as a channelopathy. Following the section on renin–angiotensins system and finishing the special issue are two reviews highlighting the interaction of the renin–angiotensin–aldosterone system with the hypothalamic–pituitary axis through enzymatic control of local tissue glucocorticoid and mineralocorticoid hormone concentrations and the renal epithelial electrolyte transport proteins in the distal nephron and collecting duct segments which are targets for hormonal control and impact blood pressure. The adrenal mineralocorticoid and glucocorticoid hormone tissue and thus target cell concentrations are controlled not only by rate of synthesis and release but also by enzymes expressed locally in the tissues. Compared to the 11betahydroxysteroid dehydrogenase type II that ‘protects’ the mineralocorticoid receptor from illicit activation by glucocorticoids, the significance of 11bHSD-1 is less well characterized. 11bHSD-1 may generate active glucocorticoid locally in tissues of significance for blood pressure control. Hunter and Bailey present a review of current status of knowledge with comprehensive tables regarding significance of the 11bHSD-1 and 11bHSD-2 enzymes in blood pressure regulation. The discovery of rare loss-offunction mutations in the aldosterone-sensitive renal Na+ transport molecules and their intracellular controllers have shown that impaired renal sodium excretion is Current Opinion in Pharmacology 2015, 21:v–viii
viii Cardiovascular and renal
sufficient for a low-renin, salt-sensitive, pseudo-hyperaldosteronism-type of hypertension. This discovery was seminal to establish beyond reasonable doubt a primary role for renal sodium transport in blood pressure control and as a pathogenic factor in hypertension. Hummler et al. give an extensive update of knowledge on systemic and molecular control of the two Na+ transporters in the distal nephron that are specifically relevant in this context, the thiazide-sensitive Na-Cl contransporter NCC and the epithelial sodium channel ENaC. Comprehensive tables provide an in-depth overview of current status of knowledge and should be a powerful aid for interested readers. It should be obvious that the present issue contains a wealth of information on progress in target identification and pharmacological and device-based treatments for arterial hypertension directed against the kidney based on new mechanistic insight and technical innovations. We would like to thank the authors for their excellent contributions and we wish the readers a pleasant journey with
Current Opinion in Pharmacology 2015, 21:v–viii
the articles and hope the issue may inspire discussion, development of ideas and new lines of research that may benefit patients.
Conflict of interest statement Nothing declared.
References 1.
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.
2.
Heinze C, Seniuk A, Sokolov MV et al.: Disruption of vascular Ca2+-activated chloride currents lowers blood pressure. J Clin Invest 2014, 124:675-686.
3.
Crowley SD, Gurley SB, Oliverio MI et al.: Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system. J Clin Invest 2005:1092-1099.
4.
Gonzalez-Villalobos RA, Janjoulia T, Fletcher NK et al.: The absence of intrarenal ACE protects against hypertension. J Clin Invest 2013, 123(5):2011-2023.
5.
McCurley A, Pires PW, Bender SB et al.: Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med 2012, 9:1429-1433.
www.sciencedirect.com
