Endothelin in Renal Physiology and Disease

M. Barton, D. E. Kohan

• Publisher: S. Karger
• Year: 2011
• ISBN:
  9783805597951
• Topic: Medizin
• Subtopic: Nephrologie

Endothelin is a 21-amino acid peptide that exerts uniquely potent and long-lasting effects on the kidney, including regulation of water and electrolyte excretion, blood pressure, cell growth, inflammation and fibrosis. During the past 10 years, the field has evolved rapidly; we are now uncovering the potential importance of endothelin receptor antagonists (ERAs) in the treatment of kidney disease.This book reviews experimental concepts, preclinical studies and clinical data which form the basis of our current understanding of the association between endothelin and kidney disease. Acclaimed experts in pharmacology, molecular biology, physiology, cardiovascular medicine, and nephrology have contributed timely reviews dealing with renal pharmacology and physiology of endothelin, the role of endothelin in renal disease development and ERAs in preclinical studies, and the current state of clinical development of ERA therapy in renal medicine.The publication at hand will be a valuable reference source for nephrologists, internists and other healthcare professionals, renal physiologists and molecular biologists, post-doctoral researchers and students in the life sciences, as well as for scientists and decision makers in drug research and development.

Molecular Biology and Physiology of Endothelin in the Kidney

Barton M, Kohan DE (eds): Endothelin in Renal Physiology and Disease.
Contrib Nephrol. Basel, Karger, 2011, vol 172, pp 18-34

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Renal Function and Blood Pressure: Molecular Insights into the Biology of Endothelin-1

Nicolas Vignon-Zellweger^a · Susi Heiden^a ·Noriaki Emoto^{a, b}

^aDepartment of Clinical Pharmacy, Kobe Pharmaceutical University, and Kobe, Japan ^bDivision of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

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Abstract

The therapeutic implications of the actions of endothelin (ET)-1 upon renal and cardiovascular function are evident. Among other diseases, ET-1 is recognized to be involved in hypertension and renal failure and, in a rush to develop novel treatments, has been extensively studied. However, given the broad localization of the two receptors (ET_A and ET_B) and the diverse effects resulting from their activation, analysis of the role of ET-1 in kidney-regulated blood pressure remains complicated. Moreover, the actions of ET-1 depend upon the cell type and physiological situation. To add to the complexity, both receptors often activate opposing signaling pathways within a single cell. Thus, until recently, reliable insights into the respective involvement of both receptors in the physiology and pathology of the kidney were eagerly awaited. These have been obtained using mice that are genetically modified for different members of the ET system. In this article, the molecular biology of ET-1 and its receptors in the control of renal vasculature tonicity, glomerular function, and management of water and salt reabsorption is discussed. The role of renal ET-1 in the context of blood pressure regulation will be discussed, and the potential of utilizing ET receptor antagonism in the treatment and prevention of glomerular and proteinuric diseases is also outlined.

Copyright © 2011 S. Karger AG , Basel

Endothelin (ET)-1 is an autocrine- and paracrine-signaling hormone involved in various physiological functions, as well as in pathological alterations of the kidney. It has proven implications in many diseases, from hypertension and renal failure to diabetes-induced end-organ damage. At the cellular level, ET-1 influences proliferation, contraction, metabolism, and apoptosis - particularly in the kidney.

The active 21-amino-acid ET-1 is processed from a prohormone by ET-converting enzymes, and produces its biological effects after interaction with two G protein-coupled receptors, ET_A and ET_B.

Genetically manipulated animals represent a powerful tool for understanding gene function in vivo. Therefore, this review pays particular attention to genetic mouse models of the ET system within the scope of kidney function and hypertension. In mice, systemic knockout (KO) of any of the ET system components leads to death at birth or early in life, demonstrating that a functioning ET system is a prerequisite for correct embryogenesis. Nevertheless, diverse genetic technologies have been used to obtain living adult KO mice. For instance, transgenic expression of ET_B in enteric nervous system precursors in mice with otherwise systemic inactivation of the ET_B gene could be used to prevent potentially lethal megacolon formation [1]. In addition, tissue-specific KO of ET-1 and its receptors in renal cells have led to viable offspring [2], and KO mice heterozygous for ET-1 have been generated [3]. These strategies have allowed the analysis of ET-1 function and the opportunity to characterize its receptors in vivo.

How Endothelin-1 Regulates Blood Pressure through Kidney Function

In the physiological state, ET-1 participates in the maintenance of vascular tone, and is often described as one of the most powerful vasoconstrictor agents. Indeed, infusion of exogenous ET-1 leads to a strong elevation of blood pressure [4]. In mice, ET-1 deficiency (restricted to the endothelial cells) reduces blood pressure, confirming the constrictive role of ET-1 upon the vasculature [5]. Nevertheless, mice overexpressing ET-1 in the endothelial cells are normotensive, and develop only moderate salt-sensitive hypertension [6]. Moreover, heterozygous ET-1 KO mice are slightly hypertensive [3]. Even though ET-1 participates in maintaining a positive vascular tone, this phenotype indicates that ET-1 plays a minor role in controlling blood pressure through its vasoconstrictive effect, at least in mice with a chronic ET-1 deficiency. The net effect of ET-1 on blood pressure seems to be rather negative. In line with this are findings that systemic and endothelial-cell-specific overexpressions of ET-1 do not influence blood pressure [7, 8]. The hypertensive phenotype in heterozygous ET-1 KO mice was first attributed to the central action of ET-1 on cardiovascular function and possible compensatory mechanisms, like ET-1-induced activation of endothelial nitric oxide synthase (eNOS) in endothelial cells [9]. Given that the kidney is the organ with the strongest expression of ET-1, we believe that the renal effects of ET-1 play a predominant role in the control of blood pressure.

Endothelin-1 Modulates Renal Function through Its Role as a Vasoconstrictor in the Renal Vasculature

ET-1 is typically produced by the endothelial cells of the renal vasculature. As in the rest of the vasculature, ET_A is present on both the smooth muscle and endothelial cells, while ET_B expression is restricted to endothelial cells [10]. Physiological doses of ET-1 contribute to the renal vascular tone, and thereby regulate glomerular pressure [11].

The glomerular filtration rate (GFR) depends greatly on the constriction of afferent and efferent arterioles. Whether ET-1 has a contractive effect predominantly upon afferent or efferent arterioles remains under dispute. Seminal studies have shown that ET-1 sensitivity is relatively greater in afferent than in efferent arterioles, indicating that ET-1 may reduce the GFR [12]. Using isolated cortical arterioles from ET_B-deficient mice, Schildroth et al. [13] elegantly showed that ET_A participates in the contraction of afferent and efferent arterioles, whereas ET_B activation has no effect on afferent arterioles, but induces NO-mediated vasodilatation in efferent arterioles. This study suggests that ET-1 preferentially constricts afferent arterioles and diminishes the GFR. In line with these observations, infusion of ET-1 also slightly reduces the GFR in humans [14]. Denton et al. [15] showed that infusion of ET-1 constricts both afferent and efferent arterioles in rabbits. However, this did not modify the GFR, but did increase the filtration fraction - thereby suggesting increased glomerular pressure. They explained these results by the fact that the glomerular efferent arterioles have smaller diameters than afferent ones, and therefore ET-1 constriction may have a bigger effect on the resistance of efferent vessels. Moreover, ET_A-specific blockade elevates renal plasma flow and reduces filtration fraction, but does not affect GFR in CKD patients. This may be accompanied by a reduced glomerular pressure, again suggesting that ET-1 preferentially constricts efferent arterioles [16, 17]. The inconsistent observations regarding the constrictor actions of ET-1 in afferent and efferent arterioles may be explained by different experimental set-ups (isolated arterioles vs. in vivo infusion studies) and species-related differences (mouse, rabbit and human).

ET_B on endothelial cells counters the effect of ET_A, and participates in tonic vasodilatation via activation of eNOS and the release of prostaglandins [18]. However, ET_B antagonists have little effect on renal blood flow and GFR in rodents and humans [17, 19, 20].

The impact of ET_B differs according to whether it is present on the microvasculature of the cortical or juxtamedullary glomeruli. In contrast to cortical ET_B, ET_B on both afferent and efferent arterioles of perfused juxtamedullary nephrons mediate constriction under normal conditions [21]. In the same in vitro system, ET_B can nevertheless mediate vasodilatation in afferent arterioles of mice fed a high-salt diet [22]. The authors ascribe this vasodilatory response to the increased ET_B expression induced by the diet.

Renal infusion of ET-1 reduces cortical blood flow, yet has no effect on medullar blood flow, even though the diameter of the juxtamedullary arterioles is reduced. This can be explained by the fact that ET-1 constriction has a lower impact on the resistance of juxtamedullary vessels compared to cortical arterioles, due to their larger resting diameter. Moreover, juxtamedullary arterioles may only marginally affect medullary blood flow [15].

The vasa recta are branches of efferent arterioles that perfuse the renal medulla. Therefore, regulation of vasa recta contraction plays a major role in medullary blood flow and w...