ENDOTHELIN: AN IMPORTANT FACTOR IN ACUTE RENAL FAILURE?

doi:10.1016/S0140-6736(88)90243-7

The Lancet

Volume 332, Issue 8621, 19 November 1988, Pages 1179-1182

https://doi.org/10.1016/S0140-6736(88)90243-7 Get rights and content

Abstract

Very low concentrations of the vasoconstrictor peptide endothelin cause intense long-lasting renal vasoconstriction. In the isolated perfused rat kidney, the concentration of endothelin required to reduce blood-flow by 50% is 200 pmol/l, compared with 1000 pmol/l angiotensin II (previously the most potent known vasoconstrictor). Whereas angiotensin II has little effect on the glomerular filtration rate (GFR), a rise in endothelin from 100 to 800 pmol/l reduces GFR by 90%. Endothelin is probably present in the circulation at low concentrations in vivo; events associated clinically with acute renal failure would tend to increase this concentration. Endothelin may be a mediator in the pathogenesis of acute renal failure.

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Fluid overload has been associated with a higher risk of end-stage kidney disease in observational studies.12,13 Correction of extracellular volume expansion through natriuresis and diuresis, resulting in amelioration of microcirculation in the kidney secondary to a reduction in venous pressure and interstitial pressure, has some credence as a mechanism by which SGLT2 inhibition may improve kidney outcomes.14 In addition to volume reduction, increases in hematocrit and hemoglobin also may reflect increased erythropoiesis.
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ETA and ETB receptors are located in many parts of kidney and mediate the ET-1 response by opposite actions except in the afferent arteriole [22] (Fig. 3). Both studies in vitro and in vivo suggested that ET-1 plays an important role for pre-glomerular and post-glomerular vasoconstriction [68] and decreases renal blood flow and results in glomerular filtration decline [69–71]. Moreover, ET-1 increases urinary excretion of sodium by inhibiting tubular Na+/K+-ATPase activity in the proximal tubule and collecting ducts [72].
Endothelins including its most abundant isoform, endothelin-1 (ET-1), are peptides acting as vasoconstrictors when binding to ET_A and ET_B receptors, and, in addition to their distinct roles in normal physiology, endothelins have a central role in the pathophysiology of many diseases including cardiovascular and renal diseases. Endothelin-1 (ET-1), the most potent vasoconstrictor in the cardiovascular system, regulates basal vascular tone and glomerular hemodynamics. ET-1 is involved also in vascular and cardiac hypertrophy, inflammation, and in the development and progression of cardiovascular diseases - e.g. essential hypertension, atherosclerosis, coronary artery disease, congestive heart failure, pulmonary arterial hypertension and cerebrovascular disease and renal diseases - e.g. acute renal failure, polycystic kidney disease and chronic kidney disease. Not surprisingly, the ET system has become a target for therapeutic interventions that now include a few already established and some new promising agents. In this narrative review, we summarize physiologic properties of the ET system, focusing especially on ET-1, and its role in the pathophysiology of ET system activated diseases, and discuss the potentials of therapeutic interventions targeting the ET system in cardiovascular and renal diseases. While ET receptor antagonists have already revolutionized the management of idiopathic pulmonary arterial hypertension, so far, this class of drugs have failed as medication for congestive heart failure. Clinical trials continue to explore new applications of endothelin receptor antagonists in treatment-resistant hypertension and chronic kidney disease and have shown some benefits in the latter group by reducing proteinuria; however, they have not been approved yet. We conclude that larger clinical trials are needed to validate the use of ET receptor antagonists in ET system activated diseases.
Endothelin and Tubulointerstitial Renal Disease
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Shortly after the discovery of ET as a very potent vasoconstrictor, it was suggested that this peptide plays an important role in the pathogenesis of AKI.4
All components of the endothelin (ET) system are present in renal tubular cells. In this review, we summarize current knowledge about ET and the most common tubular diseases: acute kidney injury (AKI) and polycystic kidney disease. AKI originally was called acute tubular necrosis, pointing to the most prominent morphologic findings. Similarly, cysts in polycystic kidney disease, and especially in autosomal-dominant polycystic kidney disease, are of tubular origin. Preclinical studies have indicated that the ET system and particularly ET_A receptors are involved in the pathogenesis of ischemia-reperfusion injury, although these findings have not been translated to clinical studies. The ET system also has been implicated in radiocontrast-dye–induced AKI, however, ET-receptor blockade in a large human study was not successful. The ET system is activated in sepsis models of AKI; the effectiveness of ET blocking agents in preclinical studies is variable depending on the model and the ET-receptor antagonist used. Numerous studies have shown that the ET system plays an important role in the complex pathophysiology associated with cyst formation and disease progression in polycystic kidney disease. However, results from selective targeting of ET-receptor subtypes in animal models of polycystic kidney disease have proved disappointing and do not support clinical trials. These studies have shown that a critical balance between ET_A and ET_B receptor action is necessary to maintain structure and function in the cystic kidney. In summary, ETs have been implicated in the pathogenesis of several renal tubulointerstitial diseases, however, experimental animal findings have not yet led to use of ET blockers in human beings.
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Occasional SurveyENDOTHELIN: AN IMPORTANT FACTOR IN ACUTE RENAL FAILURE?

Abstract

Am J Med

Lancet

Am J Med

Kidney Int

Lancet

Lancet

Kidney Int

Studies of the renal circulation

Micropuncture study of acute renal failure following temporary renal ischemia in the rat

Kidney Int

Norepinephnne-induced acute renal failure: a reversible ischemic model of acute renal failure

Kidney Int

Intrarenal hemodynamics in glycerol-induced myohemoglobinuric acute renal failure in the rat

Circ Res

Acute oliguric renal failure in man: evidence for preferential renal cortical ischemia

Medicine

Nature of the renal injury following total renal ischemia in man

J Clin Invest

Renal hemodynamics m acute renal failure after shock in man

Kidney Int

A novel potent vasoconstrictor peptide produced by vascular endothelial cells

Nature

Effect of phenoxybenzamine on glycerol-induced acute renal failure in the rat

Fed Proc

Alleviation of acute anoxic renal failure m rats by β1-adrenergic blockade with practolol

Isr J Med Sci

Occasional Survey
ENDOTHELIN: AN IMPORTANT FACTOR IN ACUTE RENAL FAILURE?

Alleviation of acute anoxic renal failure m rats by β₁-adrenergic blockade with practolol