Endothelium-derived ET-1 and the development of renal injury

Miguel, Carmen De; Pollock, David M.; Pollock, Jennifer S.

doi:10.1152/ajpregu.00142.2015

Cited by 12 publications

(10 citation statements)

References 40 publications

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“…Using a model of mouse lacking ET-1 specifically in vascular endothelial cells (VEET KO mice), these investigators demonstrated that the lack of endothelium-derived ET-1 not only attenuated proximal tubular injury in response to I/R, but also decreased inflammatory and oxidative stress responses. These results suggest that ET-1 produced by the vascular endothelium acts in a paracrine manner on neighboring epithelial cells to induce renal injury [32]. Results from our own laboratory support these observations.…”

Section: Introductionsupporting

confidence: 63%

Endothelin-1 and the kidney

Miguel

Speed²,

Kasztan³

et al. 2016

Current Opinion in Nephrology and Hypertension

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Purpose of review The role of endothelin-1 (ET-1) in the kidney has been under study for many years; however, the complex mechanisms by which endothelin controls the physiology/pathophysiology of this organ are not fully resolved. This review aims to summarize recent findings on the field, especially regarding glomerular and tubular damage, Na+/water homeostasis and sex differences in ET-1 function. Recent findings Podocytes have been recently identified as a target of ET-1 in the glomerular filtration barrier via ETA receptor (ETAR) activation. Activation of ETAR by ET-1 leads to renal tubular damage by promoting endoplasmic reticulum stress and apoptosis in these cells. In addition, high flow rates in the nephron in response to high salt intake induce ET-1 production by collecting ducts and promote nitric oxide dependent natriuresis through ENaC inhibition. Recent evidence also indicates that sex hormones regulate the renal ET-1 system differently in males and females, with estrogen suppressing renal ET-1 production and testosterone upregulating that production. Summary Based on the reports reviewed in here, targeting of the renal ET system is a possible therapeutic approach against the development of glomerular injury. More animal and clinical studies are needed to better understand the dimorphic control of this system by sex hormones.

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Section: Introductionsupporting

confidence: 63%

Endothelin-1 and the kidney

Miguel

Speed²,

Kasztan³

et al. 2016

Current Opinion in Nephrology and Hypertension

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“…Moreover, data from our laboratory has shown a protective role of ET B receptor activation in tunicamycin-induced renal tubular apoptosis. 60 Thus, our results suggest that the albuminuria observed in HbSS mice treated with the dual ET A/B receptor antagonist is a combination of glomerular and tubular injury or dysfunction.…”

Section: Discussionmentioning

confidence: 57%

Long-Term Endothelin-A Receptor Antagonism Provides Robust Renal Protection in Humanized Sickle Cell Disease Mice

Kasztan

Fox

Speed

et al. 2017

JASN

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Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because of the lack of efficacious treatments targeting renal manifestations of the disease. Here, we describe a long-term treatment strategy with the selective endothelin-A receptor (ET) antagonist, ambrisentan, designed to interfere with the development of nephropathy in a humanized mouse model of SCD. Ambrisentan preserved GFR at the level of nondisease controls and prevented the development of proteinuria, albuminuria, and nephrinuria. Microscopy studies demonstrated prevention of podocyte loss and structural alterations, the absence of vascular congestion, and attenuation of glomerulosclerosis in treated mice. Studies in isolated glomeruli showed that treatment reduced inflammation and oxidative stress. At the level of renal tubules, ambrisentan treatment prevented the increased excretion of urinary tubular injury biomarkers. Additionally, the treatment strategy prevented tubular brush border loss, diminished tubular iron deposition, blocked the development of interstitial fibrosis, and prevented immune cell infiltration. Furthermore, the prevention of albuminuria in treated mice was associated with preservation of cortical megalin expression. In a separate series of identical experiments, combined ET and ET receptor antagonism provided only some of the protection observed with ambrisentan, highlighting the importance of exclusively targeting the ET receptor in SCD. Our results demonstrate that ambrisentan treatment provides robust protection from diverse renal pathologies in SCD mice, and suggest that long-term ET receptor antagonism may provide a strategy for the prevention of renal complications of SCD.

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“…ET-1 is a 21 amino acid peptide that is described as a vasoconstrictor, autocrine/paracrine mitogen and suppressor of apoptosis in the human body (de Miguel et al 2015, Shichiri et al 2000, Tsai et al 2015.…”

Section: Introductionmentioning

confidence: 99%

Roles of miR-31 and Endothelin-1 in Psoriasis Vulgaris: Pathophysiological Functions and Potential Biomarkers

Borská¹,

Andrýs²,

Chmelařová³

et al. 2017

Physiol Res

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Psoriatic lesions are characterized by hyperproliferation, aberrant differentiation of keratinocytes resistant to apoptosis and inflammation. miR-31 plays pro-proliferative, pro-differentiative and pro-inflammatory roles and modulates apoptosis in psoriatic keratinocytes. Endothelin-1 (ET-1) is produced by psoriatic keratinocytes and suppresses apoptosis. Inflammation increases the production of ET-1, which in turn leads to the chronic stimulation of keratinocyte proliferation. The aim of this study was to identify the putative link between two potential biomarkers (miR-31 and ET-1) in patients with psoriasis. The study design included experimental group (29 patients with psoriasis), and the control group (22 blood donors). The PASI score evaluated the state of the disease (median: 18.6; interquartile range 14.5-20.9). Both, the serum level of ET-1 and the whole blood level of miR-31 were significantly increased (p<0.001 and p<0.05, respectively) in patients compared to the controls. However, a significant negative relationship between ET-1 and miR-31 was observed (Spearman’s rho=-037, p=0.05). It is possible that a negative feedback loop will be present between miR-31 and ET-1. Our results indicate that miR-31 and ET-1, potential biomarkers of the disease, play significant roles in the pathophysiology of psoriasis.

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Endothelium-derived ET-1 and the development of renal injury

Cited by 12 publications

References 40 publications

Endothelin-1 and the kidney

Endothelin-1 and the kidney

Long-Term Endothelin-A Receptor Antagonism Provides Robust Renal Protection in Humanized Sickle Cell Disease Mice

Roles of miR-31 and Endothelin-1 in Psoriasis Vulgaris: Pathophysiological Functions and Potential Biomarkers

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