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  • This study appears to provide an additional example

    2021-09-09

    This study appears to provide an additional example, albeit an unanticipated one, of the importance of renal ETB receptor function in the normal control of blood pressure and salt and water homeostasis. ETB receptor-deficient rats, collecting duct-specific ETB receptor knockout mice, and rats chronically treated with an ETB receptor antagonist all display an elevation of arterial pressure that is exaggerated when the animals are placed on a high-salt diet. Although these effects may be at least partially attributable to loss of ETB receptor-mediated NO production, the work of Zeng and colleagues would suggest that impairment of D receptor-induced natriuresis might also contribute to the hypertension observed in those animals. Since D and ETB receptors are both expressed by medullary collecting duct cells, it would be interesting to know whether collecting duct-specific ETB receptor knockout mice display reduced diuretic and natriuretic responses to D receptor agonists. Although further experiments are needed to determine definitively whether D–ETB receptor heterodimers exist, for example, by using fluorescence resonance L-NMMA citrate sale transfer analysis or co-immunoprecipitation of receptors, the results of the study by Zeng and colleagues appear to indicate that D–ETB receptor interactions in the renal tubules facilitate D agonist-induced natriuresis. Zeng and colleagues have previously reported that ETB and AT receptors can be co-immunoprecipitated from SHR and WKY renal proximal tubular cells. Although Zeng and colleagues reported that stimulation of either the ETB or the AT receptor resulted in changes in expression and phosphorylation of the other receptor, the physiological consequences of these ETB–AT receptor interactions were not directly addressed. An intriguing possibility is that endothelin receptor–AT receptor heterodimerization could be one of the mechanisms underlying the reported ability of endothelin receptor antagonists to attenuate or abolish acute and chronic effects of angiotensin II (see, for example, Riggleman ). Several studies suggest that ETA receptor activation may impair α-adrenoceptor-mediated responses. However, this appears to occur, at least in fibroblasts, via phosphorylation of the α-adrenoceptor, and, as ET-1 did not stimulate internalization of the α-adrenoceptor, this effect may not involve the existence of ETA receptor–α-adrenoceptor heterodimers. A pictorial summary of the endothelin receptor dimers proposed to date is given in . Whether endothelin receptors form heterodimers with any other receptors, and the functional consequences of any such interactions, remains an open field of future inquiry. DISCLOSURE
    ACKNOWLEDGMENTS
    Introduction Status epilepticus (SE, a prolonged seizure activity) is a high risk factor of developing acquired epilepsy and permanent neurologic defects (Hesdorffer et al., 1998, Temkin, 2001, Jacobs et al., 2009). SE impairs brain-blood barrier (BBB), which plays an important role in maintaining the brain homeostasis. The development of vasogenic brain edema contributes secondary brain injury evoked by SE (van Vliet et al., 2007, Kim et al., 2010, Kim et al., 2013). For example, vasogenic edema leads to neuronal hyperexcitability, astroglial loss/dysfunction and impairment of potassium homeostasis (Ivens et al., 2007, Cacheaux et al., 2009, David et al., 2009, Friedman et al., 2009, Kim et al., 2010, Kim et al., 2013). Therefore, the inhibition of vasogenic edema formation or maintenance of BBB integrity is one of the therapeutic strategies, which would abrogate the development of acquired epilepsy and/or secondary complications induced by SE. Recently, we have reported that SE impairs BBB integrity via tumor necrosis factor (TNF)-α/nuclear factor-κB (NFκB) p65-Thr435/endothelin 1 (ET-1)/endothelin B (ETB) receptor axis, which disrupts BBB elements by endothelial nitric oxide synthase (eNOS) and/or matrix metalloproteinase-9 in the rat piriform cortex (PC; Kim et al., 2013, Kim et al., 2014, Kim et al., 2015). In this process, transient receptor potential canonical channel-3 (TRPC3) regulates NFκB phosphorylation in a positive feedback manner independent of ETB receptor-mediated signal pathway (Min and Kang, 2016). Therefore, we have suggested that the TNF-α/NFκB/TRPC3 circuit may play an important role in vasogenic edema formations following SE, although little is known about the mechanism underlying TRPC3 action on the NFκB phosphorylation. Besides this signaling pathway, up-regulated p38 mitogen-activated protein kinase (MAPK)/vascular endothelial growth factor (VEGF) pathway is another axis of SE-induced vasogenic edema formation (Kim et al., 2016). Indeed, VEGF (also known as vascular permeability factor; Goldman et al., 1997, Schoch et al., 2002) increases vascular permeability through eNOS activation (Fischer et al., 1999, Mayhan, 1999, Fukumura et al., 2001). Since endothelial TRPC3 is involved in vasodilation via NO release (Huang et al., 2011) and a downstream target of VEGF signaling (Pocock et al., 2004, Cheng et al., 2006, Poteser, 2006), it is likely that TRPC3 may link p38 MAPK/VEGF pathway to NFκB/ETB receptor axis during vasogenic edema formation. Here, we demonstrate that VEGF can activate TRPC3 followed by phosphatidylinositol 3 kinase (PI3K)/AKT/eNOS activation. Furthermore, ETB receptor also regulates PI3K/AKT phosphorylations independent of TRPC3 activation. Therefore, these findings suggest that PI3K/AKT may be regulated by TRPC3 and ETB receptor signaling pathways during vasogenic edema formation. Thus, PI3K/AKT may be common down-stream signaling molecules for both signaling pathways, which play a pivotal role in vasogenic edema formation via eNOS activation.