Expression of the bumetanide-sensitive Na-K-Cl cotransporter BSC2 is differentially regulated by fluid mechanical and inflammatory cytokine stimuli in vascular endothelium.

Topper, James N.; Wasserman, Scott M.; Anderson, Keith R.; Cai, Jiexing; Falb, Dean; Gimbrone, Michael A.

doi:10.1172/jci119489

Cited by 58 publications

(53 citation statements)

References 41 publications

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“…The nitric oxide generated by iNOS could also be directly involved in the initiation and progression of the BE (Sharma et al, 2006) and/or cerebral hyperemia (Brian et al, 1996). Increased iNOS in the CPE also has the potential to disrupt ion transport, given the fact that the Na-K-Cl cotransporter is regulated by inflammatory cytokines (Topper et al, 1997). In contrast, the up regulation of ICAM-1 is unlikely to be mediated by iNOS (Hickey et al, 2006); but likely to be the result of a direct activation by DKA.…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammatory response of the choroid plexus epithelium in fatal diabetic ketoacidosis

Hoffman

Casanova

Cudrici

et al. 2007

Experimental and Molecular Pathology

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A systemic inflammatory response (SIR) occurs prior to and during the treatment of severe diabetic ketoacidosis (DKA). IL-1β, TNF-α and C5b-9 are components of SIR and have been speculated to be involved in the clinical brain edema (BE) of DKA. We studied IL-1β, TNF-α, C5b-9, inducible nitric oxide (iNOS), ICAM-1, IL-10 and Hsp70 expression in the brains of two patients who died as the result of clinical BE during the treatment of DKA. IL-1β was strongly expressed in the choroid plexus epithelium (CPE) and ependyma, and to a lesser extent in the hippocampus, caudate, white matter radiation of the pons, molecular layer of the cerebellum and neurons of the cortical gray matter. TNF-α was expressed to a lesser extent than IL-1 β, and only in the CP. C5b-9, previously shown to be deposited on neurons and oligodendrocytes, was found on CPE and ependymal cells. iNOS and ICAM-1 had increased expression in the CPE and ependyma. Hsp70 and IL-10 were also expressed in the CPE of the case with the shorter duration of treatment. Our data demonstrates the presence of a multifaceted neuroinflammatory cytotoxic insult of the CPE, which may play a role in the pathophysiology of the fatal brain edema of DKA.

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Section: Discussionmentioning

confidence: 99%

Neuroinflammatory response of the choroid plexus epithelium in fatal diabetic ketoacidosis

Hoffman

Casanova

Cudrici

et al. 2007

Experimental and Molecular Pathology

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“…The mechanism, as well as the physiological importance of variations in venous capacitance by furosemide is unknown; it is even not known whether this is mediated via the NKCC transporters. In one study, in human umbilical vein endothelial cells, NKCC2 gene expression was induced by inflammatory cytokines, but whether such induction is present in intact veins and is physiologically significant is unknown (157).…”

Section: F962mentioning

confidence: 99%

Everything we always wanted to know about furosemide but were afraid to ask

Huang

Mees

Vos

et al. 2016

American Journal of Physiology-Renal Physiology

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Huang X, Dorhout Mees E, Vos P, Hamza S, Braam B. Everything we always wanted to know about furosemide but were afraid to ask. Am J Physiol Renal Physiol 310: F958 -F971, 2016. First published February 24, 2016 doi:10.1152/ajprenal.00476.2015.-Furosemide is a widely used, potent natriuretic drug, which inhibits the Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC)-2 in the ascending limb of the loop of Henle applied to reduce extracellular fluid volume expansion in heart and kidney disease. Undesirable consequences of furosemide, such as worsening of kidney function and unpredictable effects on sodium balance, led to this critical evaluation of how inhibition of NKCC affects renal and cardiovascular physiology. This evaluation reveals important knowledge gaps, involving furosemide as a drug, the function of NKCC2 (and NKCC1), and renal and systemic indirect effects of NKCC inhibition. Regarding renal effects, renal blood flow and glomerular filtration rate could become compromised by activation of tubuloglomerular feedback or by renin release, particularly if renal function is already compromised. Modulation of the intrarenal renin angiotensin system, however, is ill-defined. Regarding systemic effects, vasodilation followed by nonspecific NKCC inhibition and changes in venous compliance are not well understood. Repetitive administration of furosemide induces short-term (braking phenomenon, acute diuretic resistance) and long-term (chronic diuretic resistance) adaptations, of which the mechanisms are not well known. Modulation of NKCC2 expression and activity in kidney and heart failure is ill-defined. Lastly, furosemide's effects on cutaneous sodium stores and on uric acid levels could be beneficial or detrimental. Concluding, a considerable knowledge gap is identified regarding a potent drug with a relatively specific renal target, NKCC2, and renal and systemic actions. Resolving these questions would increase the understanding of NKCCs and their actions and improve rational use of furosemide in pathophysiology of fluid volume expansion. extracellular fluid volume; natriuresis; renal function; chronic kidney disease; heart failure DIURETICS BLOCKING THE Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC) have an important place in the treatment of fluid overload, specifically in the context of kidney disease and heart failure (64). Of the drugs that inhibit the NKCC2 in the loop of Henle (furosemide, bumetanide, torsemide, ethacrynic acid), furosemide is most commonly applied (66) and Ͼ40 million prescriptions are dispensed every year in the USA (66a). However, many uncertainties remain about intrarenal and systemic actions of furosemide, including its two main targets NKCC1 and NKCC2.Clinically, there are a number of undesirable consequences of the use of furosemide, of which the pathophysiological mechanisms have not been sufficiently investigated. Furosemide has been associated with worsening of kidney function in patients treated for volume overload admitted for acute heart failure (104) and even glomerular filtration rate (GFR) ...

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“…Vascular MADs represent a class of signaling molecules selectively expressed in vascular endothelium that may function in mediating responses to both the TGF-␤ superfamily of humoral factors and biomechanical forces within the vasculature. Vascular MADs may play a critical role in the ability of endothelium to integrate these diverse stimuli and thus be relevant to a variety of physiologic and pathophysiologic processes in the cardiovascular system (23).…”

mentioning

confidence: 99%

Vascular MAD s: Two novel MAD -related genes selectively inducible by flow in human vascular endothelium

Topper

Cai

Qiu

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

299

252

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Expression of the bumetanide-sensitive Na-K-Cl cotransporter BSC2 is differentially regulated by fluid mechanical and inflammatory cytokine stimuli in vascular endothelium.

Cited by 58 publications

References 41 publications

Neuroinflammatory response of the choroid plexus epithelium in fatal diabetic ketoacidosis

Neuroinflammatory response of the choroid plexus epithelium in fatal diabetic ketoacidosis

Everything we always wanted to know about furosemide but were afraid to ask

Vascular MAD s: Two novel MAD -related genes selectively inducible by flow in human vascular endothelium

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