Endothelin Receptor Subtype B Mediates Autoinduction of Endothelin-1 in Rat Mesangial Cells

Iwasaki, Shigeki; Homma, Teiichi; Matsuda, Yuzuru; Kon, Valentina

doi:10.1074/jbc.270.12.6997

Cited by 79 publications

(37 citation statements)

References 57 publications

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“…Similar increases in ET B gene expression have been reported in the pulmonary arteries of patients with chronic thromboembolic pulmonary hypertension (44). The ET B signaling pathway has been linked to the regulation of ppET-1 gene expression in rat mesangial cells (19). The present study confirms this notion since, in a previous study, we showed that ppET-1 gene expression in the main pulmonary artery was decreased in hypertensive sheep compared with controls.…”

Section: Discussionsupporting

confidence: 80%

ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

Balyakina

Chen²,

Lawrence³

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Exposure to exogenous ET-1 for 18 h revealed that only the L2 cells internalized ET-1, and internalization by hypertensive L2 cells was significantly reduced when compared with controls. Treatment with ET A (BQ-610) and ETB (BQ-788) receptor antagonists demonstrated that both receptors contributed to internalization of ET-1 in control L2 cells, whereas in hypertensive cells only when both receptor antagonists were used in combination was significant suppression of ET-1 internalization found. We conclude that in sheep receiving CAE, alterations in ET B receptors in cells of the L2 layer may contribute to the maintenance of CPH via alterations in their expression, distribution, and activity.ET A receptor; ETB receptor; smooth muscle cells; pulmonary hypertension; endothelin SINCE ITS DISCOVERY 12 YEARS AGO, endothelin (ET) has been shown to contribute to a wide variety of physiological and pathophysiological processes in various systems (22). The ET family of 21 amino acid peptides exists in three distinct isoforms: ET-1, ET-2, and ET-3. It is an extremely potent vasoconstrictor resulting in slowly developing and sustained contraction. Although the endothelial cell was originally described as the source of ET-1, it is now known that several other cell types, including pulmonary vascular smooth muscle cells, synthesize this peptide (33, 36).The biological effects of ET-1 are mediated by two distinct ET receptor subtypes, ET A and ET B (1, 35). The affinity of the ET A receptor for ET-1 has been shown to be ϳ100 times that for ET-3 (ET-1 Ͼ ET-2 Ͼ ET-3), whereas the affinity of the ET B receptor is equipotent for all three isoforms of ET (34). Early reports indicated that the ET A receptor on smooth muscle was responsible for the vasoconstrictor effect of ET-1, whereas the ET B receptor on endothelial cells modulated ET-1-induced vasodilation. However, recent pharmacological studies suggest that there are two classes of ET B with cell specific effects, ET B1 on endothelial cells mediating vasodilation and ET B2 on smooth muscle cells mediating vasoconstriction (9). The ET B receptor also functions as a "clearance receptor" and is particularly important in the lung, where 50% of ET-1 is retained (22,29).ET-1 has been linked to the development of chronic pulmonary hypertension (CPH). Increased expression of the peptide has been demonstrated in endothelial cells of pulmonary arteries from patients with idiopathic and secondary forms of pulmonary hypertension (15), and arterial-to-venous ratios of ET-1 protein were found to be elevated above the normal range in patients with pulmonary hypertension (40). Several studies have linked increased expression of ET-1 to the development of hypoxia-induced CPH in rats (5, 24), and use of ET-1 receptor antagonists has been shown both to inhibit progression of the disease and to promote recovery (4,10,43).Although these studies support a central role for ET-1 in the pathogenesis of CPH, the picture is likely more complicated than first suspected, in that prepro-ET-1 (ppET-1) mRNA is...

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Section: Discussionsupporting

confidence: 80%

ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

Balyakina

Chen²,

Lawrence³

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…A previous study reported that a blockade of ETAR that was able to activate Gαq did not inhibit ET-1 production stimulated by ET-1 in rat mesangial cells (29). On the other hand, in a study using a rat model of congestive heart failure, the ETAR antagonist BQ-123 normalized the increased expression level of ppET-1 mRNA (32).…”

Section: Discussionmentioning

confidence: 98%

“…Because of its vasoconstrictor and growth-promoting action, numerous studies indicate that ET-1 is involved in the pathogenesis of a broad spectrum of renal and cardiovascular diseases (21,22,(25)(26)(27). Previous studies have demonstrated that ET-1 induced ET-1 production through ETAR and/or ETBR-mediated pathways, suggesting that a sustained ET-1 autocrine loop contributes to the progression of cardiovascular and renal diseases (28)(29)(30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

G.ALPHA.13 Induces PreproET-1 Gene Expression via JNK.

et al. 2002

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The endothelin B receptor (ETBR) has been shown to mediate autoinduction of endothelin-1 (ET-1). We previously reported that the ETBR interacts with G 13, a member of the heterotrimeric GTP-binding protein family.In the present study, we examined whether G 13 induces preproET-1 (ppET-1) gene transcription, which could result in ET-1 autoinduction in a renal epithelial cell line. We generated a reporter gene construct un-

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“…Whereas ET-A receptors (ETA) mediate vasoconstriction, mononuclear cell infiltration, and production of matrix proteins (1), ET-B receptors (ETB) on endothelial cells mediate endothelium-dependent vasorelaxation via nitric oxide (NO) and prostacyclin formation (2). Several other functions are also attributed to ETB, including regulation of renal sodium (Na ϩ ) and water excretion (3) and stimulation of ET-1 gene expression (4). Taking these biologic actions into consideration, it is not surprising to regard ET-1 as one of the important mediators for the progression of chronic renal injury (5,6).…”

mentioning

confidence: 99%

Endothelin A Receptor Blockade and Endothelin B Receptor Blockade Improve Hypokalemic Nephropathy by Different Mechanisms

Suga¹,

Yasui²,

Yoshihara

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Hypokalemia causes renal tubulointerstitial injury with an elevation in renal endothelin-1 (ET-1). It was hypothesized that hypokalemic tubulointerstitial injury is ameliorated by the blockade of ET-A receptors (ETA), whereas ET-B receptor (ETB) antagonism may exacerbate the injury, because ETB is thought to mediate vasodilation. Rats were fed a K ϩ -deficient diet alone (LC) or with an ETA-selective antagonist ABT-627 (LA) or an ETB-selective antagonist A-192621 (LB) for 8 wk. Control rats were on a normal K ϩ diet alone or with the ETA-selective or ETB-selective antagonists. The severity of hypokalemia was not significantly different among LA, LB, and LC. LC developed tubulointerstitial injury with an elevation of renal preproET-1 mRNA level. There was an increase in tubular osteopontin expression, macrophage infiltration, collagen accumulation, and tubular cell hyperplasia.ETA blockade significantly ameliorated all parameters for renal injury in the cortex without suppressing local ET-1 and ETA expression. By contrast, ETB blockade significantly reduced local ET-1 and ETA expression and improved the injury to a similar extent in the cortex. In the medulla, ETA or ETB blockade only partially blocked renal injury. ETA blockade did not affect BP in normokalemic or hypokalemic rats. ETB blockade induced a BP elevation with a decrease in urinary Na ϩ excretion in normokalemic but not in hypokalemic rats. These results indicate that ET-1 can mediate hypokalemic renal injury in two different ways: by directly stimulating ETA and by locally promoting endogenous ET-1 production via ETB. Thus, ETA as well as ETB blockade may be renoprotective in hypokalemic nephropathy.Endothelin-1 (ET-1) is a potent vasoconstrictive peptide originally isolated from endothelial cells, but it has since been shown to also be produced by non-endothelial cells, including renal epithelial cells and mesangial cells. ET-1 exerts its biologic actions through the activation of two different receptor isoforms. Whereas ET-A receptors (ETA) mediate vasoconstriction, mononuclear cell infiltration, and production of matrix proteins (1), ET-B receptors (ETB) on endothelial cells mediate endothelium-dependent vasorelaxation via nitric oxide (NO) and prostacyclin formation (2). Several other functions are also attributed to ETB, including regulation of renal sodium (Na ϩ ) and water excretion (3) and stimulation of ET-1 gene expression (4). Taking these biologic actions into consideration, it is not surprising to regard ET-1 as one of the important mediators for the progression of chronic renal injury (5,6). Urinary excretion of ET-1 as well as preproET-1 mRNA expression in mononuclear cells increases in patients with glomerulonephritis (7,8). Renal ET-1 levels and/or preproET-1 mRNA levels are upregulated in several experimental renal disease models of immune and nonimmune origins (5). The significance of ET-1 has been strengthened by the observation that glomerular and tubulointerstitial injury develop in preproET-1 transgenic mice despite ...

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Endothelin Receptor Subtype B Mediates Autoinduction of Endothelin-1 in Rat Mesangial Cells

Cited by 79 publications

References 57 publications

ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

G.ALPHA.13 Induces PreproET-1 Gene Expression via JNK.

Endothelin A Receptor Blockade and Endothelin B Receptor Blockade Improve Hypokalemic Nephropathy by Different Mechanisms

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